PIAS3

Gene Summary

Gene:PIAS3; protein inhibitor of activated STAT, 3
Aliases: ZMIZ5
Location:1q21
Summary:This gene encodes a member of the PIAS [protein inhibitor of activated STAT (signal transducer and activator of transcription)] family of transcriptional modulators. The protein functions as a SUMO (small ubiquitin-like modifier)-E3 ligase which catalyzes the covalent attachment of a SUMO protein to specific target substrates. It directly binds to several transcription factors and either blocks or enhances their activity. Alternatively spliced transcript variants of this gene have been identified, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:E3 SUMO-protein ligase PIAS3
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Transcription Factors
  • Signal Transduction
  • Molecular Sequence Data
  • Sumoylation
  • Protein Binding
  • Immunohistochemistry
  • beta-Globins
  • Histones
  • Apoptosis
  • Tumor Suppressor Proteins
  • Transcriptional Activation
  • Down-Regulation
  • Messenger RNA
  • Terpenes
  • Lung Cancer
  • STAT3 Transcription Factor
  • Non-Small Cell Lung Cancer
  • Vimentin
  • Single Nucleotide Polymorphism
  • Tumor Markers
  • Cell Proliferation
  • RNA Interference
  • Mutation
  • Prostate Cancer
  • RTPCR
  • Molecular Chaperones
  • Risk Factors
  • Neoplastic Cell Transformation
  • Western Blotting
  • fms-Like Tyrosine Kinase 3
  • Young Adult
  • MicroRNAs
  • Amino Acid Sequence
  • Base Sequence
  • Cancer Gene Expression Regulation
  • Chromosome 1
  • Disease Progression
  • Genome-Wide Association Study
  • Multiple Myeloma
  • Proteomics
  • Protein Inhibitors of Activated STAT
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PIAS3 (cancer-related)

Siatecka M, Soni S, Planutis A, Bieker JJ
Transcriptional activity of erythroid Kruppel-like factor (EKLF/KLF1) modulated by PIAS3 (protein inhibitor of activated STAT3).
J Biol Chem. 2015; 290(15):9929-40 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
Erythroid Kruppel-like factor (EKLF or KLF1) is a transcription factor crucial for red cell development that is directly involved in regulation of a large number of erythroid genes. EKLF serves mostly as an activator of expression of these genes; however, it can act also as a repressor. Here, we present evidence that EKLF interacts with proteins from the PIAS (protein inhibitor of activated STAT) family that convey repressive activity to EKLF in the absence of sumoylation. Our studies identify PIAS3 as a transcriptional corepressor of EKLF for at least a subset of its target genes during erythropoiesis (e.g. β-globin, α-hemoglobin stabilizing protein). We demonstrate an interaction between EKLF and PIAS proteins confirmed by in vivo coimmunoprecipitation assays with both exogenous and endogenous proteins. We identified an LXXLL signature motif located near the N terminus of PIAS proteins that, although not involved in the EKLF-PIAS3 interaction, is required for the transrepression activity. Knockdown of endogenous PIAS3 accelerates differentiation of both murine erythroleukemia cells, as well as fetal liver cells, whereas an increase in PIAS3 levels inhibits this increase. Using chromatin immunoprecipitation assays, we show that PIAS3 preferentially occupies the β-globin promoter in undifferentiated murine erythroleukemia cells. Together these results demonstrate that an interaction between EKLF and PIAS3 provides a novel mode of regulation of EKLF activity in the absence of sumolylation and furthermore shows an important involvement of PIAS proteins in erythropoiesis.

Dabir S, Kluge A, Kresak A, et al.
Low PIAS3 expression in malignant mesothelioma is associated with increased STAT3 activation and poor patient survival.
Clin Cancer Res. 2014; 20(19):5124-32 [PubMed] Related Publications
PURPOSE: Deregulation of STAT3 activation is a hallmark of many cancer cells, and the underlying mechanisms are subject to intense investigation. We examined the extent of PIAS3 expression in mesothelioma cells and human tumor samples and determined the functional effects of PIAS3 expression on STAT3 signaling.
EXPERIMENTAL DESIGN: We evaluated the expression of PIAS3 in mesothelioma tumors from patients and correlated the expression levels with the course of the disease. We also measured the effects of enhanced PIAS3 activity on STAT3 signaling, cellular growth, and viability in cultured mesothelioma cells.
RESULTS: Gene expression databases revealed that mesotheliomas have the lowest levels of PIAS3 transcripts among solid tumors. PIAS3 expression in human mesothelioma tumors is significantly correlated with overall survival intervals (P = 0.058). The high expression of PIAS3 is predictive of a favorable prognosis and decreases the probability of death within one year after diagnosis by 44%. PIAS3 expression is functionally linked to STAT3 activation in mesothelioma cell lines. STAT3 downregulation with siRNA or enhanced expression of PIAS3 both inhibited mesothelioma cell growth and induced apoptosis. Mesothelioma cells are sensitive to curcumin and respond by the induction of PIAS3. Corroborative evidence has been obtained from STAT3 inhibition experiments. Exposure of the cells to a peptide derived from the PIAS3 protein that interferes with STAT3 function resulted in apoptosis induction and the inhibition of cell growth.
CONCLUSION: These results suggest that PIAS3 protein expression impacts survival in patients with mesothelioma and that PIAS3 activation could become a therapeutic strategy. Clin Cancer Res; 20(19); 5124-32. ©2014 AACR.

Yu T, Lu Q, Ou X, et al.
Association of sedentary behavior with the expression levels of biomarkers in colorectal cancer: clinical analysis of 228 patients.
Tohoku J Exp Med. 2014; 232(3):167-76 [PubMed] Related Publications
There is an association between sedentary behavior and the risk of colorectal cancer (CRC), but the underlying mechanism is unclear. CRC is characterized by the changes in the expression levels of biomarkers, including voltage-gated proton channel Hv1, matrix-remodeling associated 5 (MXRA5), DEK (inducing positive supercoils into circular DNA) and protein inhibitor of activated signal transducer and activators of transcription 3 (PIAS3). Thus, sedentary behavior may affect the expression levels of these biomarkers in the colorectal tissue. Here, we recruited 228 CRC patients (128 males, 57.8 ± 7.8 years; 100 females, 57.7 ± 7.5 years) and 80 healthy subjects (48 males, 57.5 ± 6.8 years; 32 females, 56.9 ± 6.5 years) from March 7th, 2010 to May 6th, 2012. All the subjects were unrelated Han Chinese with the similar cultural and economic background. All the subjects were interviewed concerning sedentary time (sitting time categories: less than 1, 1-3, 4-6, and more than 6 h/day). The daily sedentary time of most CRC patients was more than 4 h/day, while the sedentary time of most healthy subjects was less than 3 h/day. The expression levels of Hv1, MXRA5 and DEK mRNAs and proteins were higher in CRC tissues and the levels of PIAS3 mRNA and protein were lower when the daily sedentary time was longer in CRC patients (p < 0.05). The daily sedentary time was correlated with the protein levels of CRC biomarkers. Furthermore, the sedentary time was positively related with body mass index but not daily calorie intake.

Zhao Z, Wu L, Shi H, Wu C
p53 N‑terminal binding and stabilisation by PIAS3 inhibits MDM2‑induced p53 ubiquitination and regulates cell growth.
Mol Med Rep. 2014; 9(5):1903-8 [PubMed] Related Publications
Mouse double minute 2 homolog (MDM2) binds to p53 through the 1-52 amino acid region of p53, in order to ubiquitinate p53. MDM2 thus destabilises p53 and inhibits the effect of p53 on cell cycle arrest and apoptosis. In the present study, the 1-52 amino acid region of the wild-type (wt) p53 protein was stably expressed in H1299 cells. The lysate of the transfected cells was then analysed using co-immunoprecipitation. A specific fraction of the precipitate was subjected to mass spectrometry analysis, which revealed that p53 bound to protein inhibitor of activated STAT3 (PIAS3). To the best of our knowledge, the present study is the first to report that the interaction of PIAS3 with p53 occurs through the 1-52 amino acid region of p53. Overexpression of PIAS3 in the A549 wt p53-expressing cell line was found to significantly increase the half‑life of p53 in the presence of cycloheximide, an inhibitor of protein synthesis. However, PIAS3 overexpression did not affect p53 mRNA levels. Furthermore, PIAS3 overexpression was observed to decrease p53 ubiquitination. Protein-protein interaction analysis revealed that PIAS3 binds to the 1-52 amino acid region of p53, thus disrupts the formation of the p53‑MDM2 complex. In addition, overexpression of PIAS3 in A549 cells was found to enhance the transcription of the p53‑transactivated target p21/waf1, due to p53 accumulation, which led to an increase in p53 binding to the p21 gene promoter. These findings indicate that this newly identified p53‑PIAS3 interaction through the 1-52 amino acid region of p53, reduces p53‑MDM2 complex formation, which not only increases the half-life of p53, but also its transactivation of target genes.

Nam D, Song J, Kim SM, et al.
8-hydrocalamenene, derived from Reynoutria elliptica, suppresses constitutive STAT3 activation, inhibiting proliferation and enhancing chemosensitization of human multiple myeloma cells.
J Med Food. 2014; 17(3):365-73 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
The identification of the active compounds of herbal medicines and the molecular targets of those compounds is an attractive therapeutic objective. Reynoutria elliptica has been used for the treatment of various inflammatory diseases as a Korean folk remedy. Based on the evidence that anti-inflammatory agents frequently exert antiproliferative activity, we tested two sesquiterpene derivatives, 8-hydrocalamenene (HC) and 8,14-dihydrocalamenene (DHC), for their ability to induce apoptosis and suppress signal transducer and activator of transcription 3 (STAT3) activation in multiple myeloma (MM) U266 cells. We found that HC inhibited cell viability in U266, but not in peripheral blood mononuclear cells. HC exerted significant cytotoxicity and induced substantial subG1-phase arrest and apoptosis as compared with DHC. HC inhibited the expression of gene products involved in antiapoptosis (Bcl-2 and Bcl-xL), proliferation (cyclin D1), and invasion (MMP-9), all of which are known to be regulated by STAT3. Furthermore, HC up-regulated cyclin-dependent kinase inhibitor p21 and induced apoptosis through the activation of caspase-8, -9, and -3 in U266 cells. Interestingly, HC blocked constitutive STAT3 activation through the inhibition of activation of upstream kinases Janus-like kinase 1 (JAK1), JAK2, and c-Src and up-regulated PIAS3. Deletion of STAT3 reversed cytotoxic effects and the down-regulation of cyclin D1 and c-myc by HC in MM cells. Finally, this sesquiterpene significantly synergized the cytotoxic and apoptotic effects of bortezomib in U266 cells. Taken together, these results suggest that HC is a novel blocker of STAT3 activation which may have a potential in the prevention and treatment of MM.

Cao Q, Li YY, He WF, et al.
Interplay between microRNAs and the STAT3 signaling pathway in human cancers.
Physiol Genomics. 2013; 45(24):1206-14 [PubMed] Related Publications
MicroRNAs (miRNAs, also miR) are a class of noncoding endogenous RNAs that regulate gene expression through binding to protein-coding messenger RNA (mRNA) molecules, predominantly within the 3'-untranslated region (3'-UTR). Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates a battery of genes involved in regulating a variety of biological processes. There is a growing body of evidence demonstrating that miRNAs are closely associated with the STAT3 signaling pathway. In this review, we focus on interactions between miRNAs and the STAT3 signaling pathway, focusing on their reciprocal regulation and roles in cancer. For instance, several papers independently support the existence of regulatory feedback loops between miRNAs and the STAT3 pathway in different cancer contexts including IL-6-STAT3-miR-24/miR-629-HNF4α-miR-124 and IL-6R-STAT3-NF-κB-Lin-28-let-7a. Furthermore, several miRNA components are reported to be involved in STAT3-mediated tumorigenesis, for example miR-21, miR-155, and miR-181b. Through binding to STAT3-binding sites within the promoters of these oncomiRs, STAT3 activates their transcription and mediates tumorigenesis. Some miRNAs directly modulate STAT3 activity through targeting the STAT3 3'-UTR; other miRNAs target SOCS, PIAS3, and EGFR genes, which encode proteins that regulate the STAT3 signaling pathway. Given that miRNAs represent a newly discovered class of regulatory molecules, investigating their biological functions and contribution to pathologies caused by STAT3 dysregulation is essential to improve our understanding of tumorigenesis and to develop novel anticancer therapeutics. The more we can learn about miRNAs-STAT3 interactions, the better able we will be to manipulate them for developing cancer therapeutics.

Wang Z, Han J, Cui Y, et al.
miRNA-21 inhibition enhances RANTES and IP-10 release in MCF-7 via PIAS3 and STAT3 signalling and causes increased lymphocyte migration.
Biochem Biophys Res Commun. 2013; 439(3):384-9 [PubMed] Related Publications
MicroRNAs (miRNAs) are a class of small endogenous gene regulators that have been implicated in various developmental and pathological processes. However, the precise identities and functions of miRNAs involved in antitumor immunity are not yet well understood. miRNA-21 is an oncogenic miRNA that can be detected in various tumours. In this study, we report that a miRNA-21 inhibitor enhances the release of chemoattractants RANTES and IP-10 in the MCF-7 breast cancer cell line and results in increased lymphocyte migration. Thus, miRNA-21 is a potential therapeutic target for cancer immunotherapy. We further demonstrated that PIAS3, a protein inhibitor of activated STAT3, is a target of miRNA-21 in MCF-7. Thus, miRNA-21 is a novel miRNA regulating immune cell recruitment, which acts at least in part via its inhibition of PIAS3 expression and oncogenic STAT3 signalling in tumour cells.

Dabir S, Kluge A, McColl K, et al.
PIAS3 activates the intrinsic apoptotic pathway in non-small cell lung cancer cells independent of p53 status.
Int J Cancer. 2014; 134(5):1045-54 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
Protein inhibitor of activated signal transducer and activator of transcription 3 (STAT3) (PIAS3) is an endogenous inhibitor of STAT3 that negatively regulates STAT3 transcriptional activity and cell growth and demonstrates limited expression in the majority of human squamous cell carcinomas of the lung. In this study, we sought to determine whether PIAS3 inhibits cell growth in non-small cell lung cancer cell lines by inducing apoptosis. Our results demonstrate that overexpression of PIAS3 promotes mitochondrial depolarization, leading to cytochrome c release, caspase 9 and 3 activation and poly (ADP-ribose) polymerase cleavage. This intrinsic pathway activation was associated with decreased Bcl-xL expression and increased Noxa expression and was independent of p53 status. Furthermore, PIAS3 inhibition of STAT3 activity was also p53 independent. Microarray experiments were performed to discover STAT3-independent mediators of PIAS3-induced apoptosis by comparing the apoptotic gene expression signature induced by PIAS3 overexpression with that induced by STAT3 siRNA. The results showed that a subset of apoptotic genes was uniquely expressed only after PIAS3 expression. Thus, PIAS3 may represent a promising lung cancer therapeutic target because of its p53-independent efficacy and its potential to synergize with Bcl-2 targeted inhibitors.

Shi L, Wan Y, Sun G, et al.
miR-125b inhibitor may enhance the invasion-prevention activity of temozolomide in glioblastoma stem cells by targeting PIAS3.
BioDrugs. 2014; 28(1):41-54 [PubMed] Related Publications
BACKGROUND: Temozolomide, an alkylating agent, is a promising chemotherapeutic agent for treating glioblastoma. Although chemotherapy with temozolomide may restrain tumor growth for some months, invariable tumor recurrence suggests that cancer stem cells maintaining these tumors persist. Previous research has shown that temozolomide can inhibit the proliferation of human glioblastoma stem cells (GSCs); however, no research has focused on the invasion of GSCs, which is an important factor for glioblastoma recurrence. Accumulating evidence indicates that microRNA (miR)-125b over-expression in GSCs may increase their invasiveness.
OBJECTIVE: Our objective was to identify the effects and mechanism of action of an miR-125b inhibitor combined with temozolomide in the invasive pathogenesis of GSCs.
METHODS: We modified the levels of miR-125b expression in primary GSCs in order to observe the effect on sensitivity to temozolomide on invasion, and we further analyzed the differences in mechanism between miR-125b treatment alone and treatment with miR-125b plus temozolomide using the Cancer PathwayFinder PCR Array.
RESULTS: Our results demonstrated that either an miR-125b inhibitor or temozolomide could modestly inhibit the invasiveness of GSCs. Furthermore, GSCs that were pre-transfected with an miR-125b inhibitor, then treated with temozolomide, showed significantly decreased invasiveness when compared with GSCs treated with an miR-125b inhibitor or temozolomide alone. Further research into the underlying mechanism demonstrated that the miR-125b inhibitor enhanced the invasion-prevention activity of temozolomide in GSCs through targeting PIAS3 (protein inhibitor of activated STAT [signal transducer and activator of transcription]), which contributed to reduced STAT3 transcriptional activity and subsequent decreased expression of matrix metalloproteinase (MMP)-2 and -9.
CONCLUSIONS: miR-125b could play a role in the development of temozolomide resistance in GSCs. Inhibition of miR-125b expression may enhance sensitivity of GSCs to temozolomide by targeting PIAS3 on cell invasion.

Wu W, Takanashi M, Borjigin N, et al.
MicroRNA-18a modulates STAT3 activity through negative regulation of PIAS3 during gastric adenocarcinogenesis.
Br J Cancer. 2013; 108(3):653-61 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
BACKGROUND: MicroRNA (miRNA, miR)-18a is a member of the miR-17-92 cluster, an important locus that is markedly overexpressed in several cancers and associated with cancer development and progression. However, the mechanism of action of the miR-17-92 cluster and its individual miRNAs are largely unknown.
METHODS AND RESULTS: In this study, we investigated the expression of the miR-17-92 cluster by in situ hybridisation (ISH) assay and copy-number analysis in gastric tissue microarray (TMA) specimens. We determined that miR-18a was present at higher levels than the other five miRNAs in the cluster. In addition, we identified Protein Inhibitor of Activated Signal Transducer and Activator of Transcription 3 (PIAS3) as a direct target of miR-18a in gastric cancer. miR-18a level was positively correlated with levels of Survivin, Bcl-xL, and c-Myc, which are downstream transcriptional targets of Signal Transducer and Activator of Transcription 3 (STAT3). STAT3-induced transcription can be negatively regulated by PIAS3; consistent with this, PIAS3 level was negatively correlated with levels of Survivin, Bcl-xL, and c-Myc.
CONCLUSION: Our findings indicate that miR-18a acts as an oncogene and plays a role in gastric adenocarcinogenesis, at least in part by negatively regulating PIAS3 and thereby modulating expression of STAT3 target genes.

Gupta SC, Phromnoi K, Aggarwal BB
Morin inhibits STAT3 tyrosine 705 phosphorylation in tumor cells through activation of protein tyrosine phosphatase SHP1.
Biochem Pharmacol. 2013; 85(7):898-912 [PubMed] Related Publications
The major goal of cancer drug discovery is to find an agent that is safe and affordable, yet effective against cancer. Here we show that morin (3,5,7,2',4'-pentahydroxyflavone) has potential against cancer cells through suppression of the signal transducer and activator of transcription 3 (STAT3) pathway, which is closely linked to the transformation, survival, proliferation, and metastasis of cancer. We found that morin completely suppressed inducible and constitutively activated STAT3 and blocked the nuclear translocation of STAT3 and its DNA binding in multiple myeloma and head and neck squamous carcinoma cells. Morin inhibited activated Src, JAK-1, and JAK-2, all of which are linked to STAT3 activation, while up-regulating a protein inhibitor of activated STAT3, PIAS3. Pervanadate reversed the effects of morin on STAT3 phosphorylation, indicating the role of a protein tyrosine phosphatase. Furthermore, morin induced SHP1 expression at both the mRNA and protein levels, and silencing of SHP1 abrogated the effect of morin on STAT3 phosphorylation, indicating that morin mediates its effects on STAT3 through SHP1. Suppression of STAT3 correlated with the down-regulation of various gene products linked to tumor survival, proliferation, and angiogenesis and led to sensitization of tumor cells to thalidomide and bortezomib. Comparing the activities of morin with those of four structurally related flavonols demonstrated the importance of hydroxyl groups in the B ring in inhibiting STAT3 activation. These findings suggest that morin suppresses the STAT3 pathway, leading to the down-regulation of STAT3-dependent gene expression and chemosensitization of tumor cells.

Xiong Q, Zhong Q, Zhang J, et al.
Identification of novel miR-21 target proteins in multiple myeloma cells by quantitative proteomics.
J Proteome Res. 2012; 11(4):2078-90 [PubMed] Related Publications
Substantial evidence indicates that microRNA-21 (miR-21) is a key oncomiR in carcinogenesis and is significantly elevated in multiple myeloma (MM). In this study, we explored the role of miR-21 in human MM cells and searched for miR-21 targets. By knocking down the expression of endogenous miR-21 in U266 myeloma cells, we observed reduced growth, an arrested cell cycle, and increased apoptosis. To further understand its molecular mechanism in the pathogenesis of MM, we employed a SILAC (stable isotope labeling by amino acids in cell culture)-based quantitative proteomic strategy to systematically identify potential targets of miR-21. In total, we found that the expression of 178 proteins was up-regulated significantly by miR-21 inhibition, implying that they could be potential targets of miR-21. Among these, the protein inhibitor of activated STAT3 (PIAS3) was confirmed as a direct miR-21 target by Western blotting and reporter gene assays. We further demonstrated that miR-21 enhances the STAT3-dependent signal pathway by inhibiting the function of PIAS3 and that down-regulation of PIAS3 contributes to the oncogenic function of miR-21. This elucidation of the role of PIAS3 in the miR-21-STAT3 positive regulatory loop not only may shed light on the molecular basis of the biological effects of miR-21 observed in MM cells but also has direct implications for the development of novel anti-MM therapeutic strategies.

Park YY, Kim K, Kim SB, et al.
Reconstruction of nuclear receptor network reveals that NR2E3 is a novel upstream regulator of ESR1 in breast cancer.
EMBO Mol Med. 2012; 4(1):52-67 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
ESR1 is one of the most important transcription factors and therapeutic targets in breast cancer. By applying systems-level re-analysis of publicly available gene expression data, we uncovered a potential regulator of ESR1. We demonstrated that orphan nuclear receptor NR2E3 regulates ESR1 via direct binding to the ESR1 promoter with concomitant recruitment of PIAS3 to the promoter in breast cancer cells, and is essential for physiological cellular activity of ESR1 in estrogen receptor (ER)-positive breast cancer cells. Moreover, expression of NR2E3 was significantly associated with recurrence-free survival and a favourable response to tamoxifen treatment in women with ER-positive breast cancer. Our results provide mechanistic insights on the regulation of ESR1 by NR2E3 and the clinical relevance of NR2E3 in breast cancer.

Liu LM, Yan MG, Yang DH, et al.
The expression of protein inhibitor of activated signal transducers and activators of transcription 3 in the evolutionary process of gastric cancer.
Eur J Intern Med. 2011; 22(5):e31-5 [PubMed] Related Publications
OBJECTIVE: To study the expression of PIAS3 (protein inhibitor of activated signal transducers and activators of transcription 3) in the evolutionary process of gastric cancer.
METHODS: Samples were taken from the endoscopic biopsy specimens of 125 patients. Gastric mucosal lesions were diagnosed in HE staining, and chronic atrophic gastritis (CAG) with intestinal metaplasia (IM) were distinguished in AB-PAS and HID-AB staining. The expressions of PIAS3 gene in different types of gastric mucosal lesions were detected by immunocytochemistry and in situ hybridization. The results were analyzed using IPP 6.0 image analysis system, from which the average optical density was obtained of positive cells.
RESULTS: There were 25 patients with chronic superficial gastritis (CSG), 87 CAG (30 with complete intestinal IM, 27 with incomplete intestinal IM, 21 with complete colonic IM, 9 with incomplete colonic IM), 8 dysplasia (DYS) and 5 gastric cancer (GC). In the expressions of PIAS3 mRNA and protein, a difference was not found between the patients with CSG and those with CAG with complete or incomplete intestinal IM; however, a significant difference was statistically found among patients with CSG (or intestinal IM), complete colonic IM, incomplete colonic IM, DYS and GC, expression levels of which stepped down one by one.
CONCLUSIONS: There are differences in the PIAS3 expression from different stages of gastric precancerous conditions/lesions to GC, which may reveal a close relationship between expression reduction or loss of PIAS3 and gastric tumorigenesis.

Kluge A, Dabir S, Vlassenbroeck I, et al.
Protein inhibitor of activated STAT3 expression in lung cancer.
Mol Oncol. 2011; 5(3):256-64 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
Protein Inhibitor of Activated Signal Transducer and Activators of Transcription 3 (PIAS3) is an endogenous inhibitor of STAT3 transcriptional activity. We have previously demonstrated the concentration-dependent negative regulatory effect of PIAS3 on STAT3 signaling and its capacity to decrease lung cancer proliferation and synergize with epidermal growth factor inhibition. We now investigate PIAS3 expression in both non-small cell lung cancer (NSCLC) cell lines and human resected NSCLC specimens. We also investigated the mechanism by which some lung cancers have significantly decreased PIAS3 expression. Expression of PIAS3 is variable in lung cancer cells lines with 2 of 3 squamous cell carcinoma (SCC) cell lines having no or little PIAS3 protein expression. Similarly, the majority of human SCCs of the lung lack PIAS3 expression by immunohistochemistry; this despite the finding that SCCs have significantly higher levels of PIAS3 mRNA compared to adenocarcinomas. High PIAS3 expression generally correlates with decreased phosphorylated STAT3 in both SCC cell lines and human specimens compatible with the negative regulatory effect of this protein on STAT3 signaling. To investigate this variable expression of PIAS3 we first performed sequencing of the PIAS3 gene that demonstrated single nucleotide polymorphisms but no mutations. Exposure of lung cancer cells to 5-azacytidine and trichostatin A results in a significant increase in PIAS3 mRNA and protein expression. However, methylation-specific PCR demonstrates a lack of CpG island methylation in the promoter region of PIAS3. Exposure of cells to an agent blocking proteosomal degradation results in a significant increase in PIAS3. Our data thus shows that SCC of the lung commonly lacks PIAS3 protein expression and that post-translational modifications may explain this finding in some cases. PIAS3 is a potential therapeutic molecule to target STAT3 pathway in lung cancer.

Dagvadorj A, Tan SH, Liao Z, et al.
N-terminal truncation of Stat5a/b circumvents PIAS3-mediated transcriptional inhibition of Stat5 in prostate cancer cells.
Int J Biochem Cell Biol. 2010; 42(12):2037-46 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
Transcription factor Stat5a/b is critical for prostate cancer cell survival and for prostate xenograft tumor growth. In addition, the Stat5a/b signaling pathway may contribute to progression of organ-confined prostate cancer to castration-resistant and/or metastatic disease. Expression of nuclear Stat5a/b is clustered to high grade human prostate cancers, and nuclear Stat5a/b in primary prostate cancer predicts early disease recurrence after initial treatment. Here, we show by Western blotting and electromobility shift assay that Stat5a/b protein in human prostate cancer is N-terminally truncated. This short form of Stat5a/b is generated post-translationally in vivo in prostate cancer cells and is the predominant form of Stat5a/b that binds to DNA. We further demonstrate by mutagenesis and co-immunoprecipitations that the N-domain of Stat5a/b is required for binding to PIAS3, and that PIAS3 inhibits transcriptional activity of Stat5a/b in breast cancer cells but not in prostate cancer cells. Thus, the proteolytic cleavage of the N-terminus of Stat5a/b may be a mechanism by which Stat5 evades the transcriptional repression by PIAS3 in prostate cancer cells, and results in increased Stat5-driven gene expression and prostate cancer progression.

Borghouts C, Tittmann H, Delis N, et al.
The intracellular delivery of a recombinant peptide derived from the acidic domain of PIAS3 inhibits STAT3 transactivation and induces tumor cell death.
Mol Cancer Res. 2010; 8(4):539-53 [PubMed] Related Publications
Signaling components, which confer an "addiction" phenotype on cancer cells, represent promising drug targets. The transcription factor signal transducers and activators of transcription 3 (STAT3) is constitutively activated in many different types of tumor cells and its activity is indispensible in a large fraction. We found that the expression of the endogenous inhibitor of STAT3, protein inhibitor of activated STAT3 (PIAS3), positively correlates with STAT3 activation in normal cells. This suggests that PIAS3 controls the extent and the duration of STAT3 activity in normal cells and thus prevents its oncogenic function. In cancer cells, however, the expression of PIAS3 is posttranscriptionally suppressed, possibly enhancing the oncogenic effects of activated STAT3. We delimited the interacting domains of STAT3 and PIAS3 and identified a short fragment of the COOH-terminal acidic region of PIAS3, which binds strongly to the coiled-coil domain of STAT3. This PIAS3 fragment was used to derive the recombinant STAT3-specific inhibitor rPP-C8. The addition of a protein transduction domain allowed the efficient internalization of rPP-C8 into cancer cells. This resulted in the suppression of STAT3 target gene expression, in the inhibition of migration and proliferation, and in the induction of apoptosis at low concentrations [half maximal effective concentration (EC(50)), <3 micromol/L]. rPP-C8 did not affect normal fibroblasts and represents an interesting lead for the development of novel cancer drugs targeting the coiled-coil domain of STAT3.

Dabir S, Kluge A, Dowlati A
The association and nuclear translocation of the PIAS3-STAT3 complex is ligand and time dependent.
Mol Cancer Res. 2009; 7(11):1854-60 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
The epidermal growth factor (EGF) receptor activation of downstream signal transducers and activators of transcription 3 (STAT3) plays a crucial role in the pathogenesis of lung cancer. STAT3 transcriptional activity can be negatively regulated by protein inhibitor of activated STAT3 (PIAS3). We investigated the time-dependent PIAS3 shuffling and binding to STAT3 in an EGF-dependent model in lung cancer by using confocal microscopy, immunoprecipitation, luciferase reporter assay, and protein analysis of segregated cellular components. We also explored the role of phosphorylation at Tyr705 of STAT3 in the formation and intracellular shuffling of the PIAS3-STAT3 complex. In a growth factor-free state, PIAS3 was localized to the cytoplasm and unbound to STAT3 in both H520 and A549 cells. On exposure to EGF, we observed STAT3 phosphorylation and rapid formation of the PIAS3-STAT3 complex. Within 5 minutes, there was a progressive translocation of the complex to the nucleus, and by 10 minutes, PIAS3 was uniquely localized to the nuclear compartment. After 30 minutes, PIAS3 returned to the cytoplasm. Using site-directed mutagenesis, we substituted Tyr705 of STAT3 with a phenylalanine. Despite EGF stimulation, we observed a significant decrease in PIAS3-STAT3 binding and a significant reduction in nuclear translocation of PIAS3. Furthermore, there was a significant reduction in the capacity of PIAS3 to reduce STAT3-mediated gene transcription. In wild-type STAT3 cells, increasing concentrations of PIAS3 resulted in a proportional decrease in STAT3 phosphorylation. These data suggest an important role for the negative regulatory effect of PIAS3 on STAT3 in EGF-driven tumors.

Dünnebier T, Bermejo JL, Haas S, et al.
Polymorphisms in the UBC9 and PIAS3 genes of the SUMO-conjugating system and breast cancer risk.
Breast Cancer Res Treat. 2010; 121(1):185-94 [PubMed] Related Publications
SUMOylation consists in the covalent conjugation of small ubiquitin-related modifiers to target proteins. SUMOylation participates in processes that are tightly linked to tumorigenesis, and genetic variability in the SUMO-conjugating system may influence the development of breast cancer. We recently reported that variation in the UBC9 gene encoding the SUMO-conjugating enzyme may affect the grade of breast tumors. Following comprehensive in silico analyses for detection of putative functional polymorphisms in 14 genes of the SUMO system, we selected one coding SNP in PIAS3 and seven tag SNPs in UBC9 for association analyses. Results were based on 1,021 cases, and 1,015 matched controls from the population-based GENICA study. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by conditional logistic regression. To explore the association with polymorphisms closely linked to the genotyped variants, multiple imputation based on HapMap data was applied. The study revealed associations of four UBC9 polymorphisms with risk of grade 1 tumors. Comparison of genotype and haplotype models indicated that the best representation of risk solely relied on rs7187167 under dominant penetrance. Women carrying the rare allele showed an increased risk of grade 1 tumors compared with common homozygotes (OR 1.87, 95% CI 1.18-2.95). This effect appeared to be stronger in women with a family history of breast or ovarian cancer. Imputation of polymorphisms in a 300-kb region around the genotyped polymorphisms identified no variants with stronger associations. Our findings suggest that genetic variation in UBC9 may affect the risk of grade 1 breast tumors.

Toujani S, Dessen P, Ithzar N, et al.
High resolution genome-wide analysis of chromosomal alterations in Burkitt's lymphoma.
PLoS One. 2009; 4(9):e7089 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
Additional chromosomal abnormalities are currently detected in Burkitt's lymphoma. They play major roles in the progression of BL and in prognosis. The genes involved remain elusive. A whole-genome oligonucleotide array CGH analysis correlated with karyotype and FISH was performed in a set of 27 Burkitt's lymphoma-derived cell lines and primary tumors. More than half of the 145 CNAs<2 Mb were mapped to Mendelian CNVs, including GSTT1, glutathione s-transferase and BIRC6, an anti-apoptotic protein, possibly predisposing to some cancers. Somatic cell line-specific CNVs localized to the IG locus were consistently observed with the 244 K aCGH platform. Among 136 CNAs >2 Mb, gains were found in 1q (12/27), 13q (7/27), 7q (6/27), 8q(4/27), 2p (3/27), 11q (2/27) and 15q (2/27). Losses were found in 3p (5/27), 4p (4/27), 4q (4/27), 9p (4/27), 13q (4/27), 6p (3/27), 17p (3/27), 6q (2/27),11pterp13 (2/27) and 14q12q21.3 (2/27). Twenty one minimal critical regions (MCR), (range 0.04-71.36 Mb), were delineated in tumors and cell lines. Three MCRs were localized to 1q. The proximal one was mapped to 1q21.1q25.2 with a 6.3 Mb amplicon (1q21.1q21.3) harboring BCA2 and PIAS3. In the other 2 MCRs, 1q32.1 and 1q44, MDM4 and AKT3 appeared as possible drivers of these gains respectively. The 13q31.3q32.1 <89.58-96.81> MCR contained an amplicon and ABCC4 might be the driver of this amplicon. The 40 Kb 2p16.1 <60.96-61> MCR was the smallest gained MCR and specifically encompassed the REL oncogene which is already implicated in B cell lymphomas. The most frequently deleted MCR was 3p14.1 <60.43-60.53> that removed the fifth exon of FHIT. Further investigations which combined gene expression and functional studies are essential to understand the lymphomagenesis mechanism and for the development of more effective, targeted therapeutic strategies.

Kluge A, Dabir S, Kern J, et al.
Cooperative interaction between protein inhibitor of activated signal transducer and activator of transcription-3 with epidermal growth factor receptor blockade in lung cancer.
Int J Cancer. 2009; 125(7):1728-34 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
Epidermal Growth Factor Receptor (EGFR) targeting in nonsmall cell lung cancer (NSCLC) is an established treatment modality; however, it only benefits a minority of patients. STAT3 (signal transducer and activator of transcription-3) plays an important role in the oncogenic signal transduction pathway of NSCLC. Inhibition of STAT3 results in NSCLC growth inhibition and apoptosis. We have previously shown that combined inhibition of EGFR and STAT3 by small molecules resulted in improved therapeutic efficacy as compared with blocking EGFR alone. However, the STAT3 protein has a number of endogenous negative regulators including PIAS3 (Protein Inhibitor of Activated STAT3). In this study, we investigated for the first time the role of PIAS3 in modulating oncogenic EGFR-STAT3 signaling pathway in lung cancer and the anti-proliferative effect of using PIAS3 in conjunction with EGFR blockade in NSCLC. We demonstrate that PIAS3 is expressed in variable degrees in all NSCLC cells. EGF and IL-6 stimulation resulted in the association of PIAS3 with STAT3. The PIAS3/STAT3 complex then bound the STAT3 DNA binding sequence resulting in STAT3 regulated gene expression. Over-expression of PIAS3, using a PIAS3 expression construct, decreases STAT3 transcriptional activity. Furthermore, over-expression of PIAS3 consistently decreased proliferation. EGFR blockade and PIAS3 over-expression in combination had significantly greater anti-proliferative effects as compared with either EGFR blockade or PIAS3 over-expression alone. In conclusion, PIAS3 is expressed in NSCLC cell lines and its over-expression decreased STAT3 transcriptional activity, decreased proliferation of NSCLC cells and when used in conjunction with EGFR inhibitors, increased the anti-proliferative effects.

Ma KW, Au SW, Waye MM
Over-expression of SUMO-1 induces the up-regulation of heterogeneous nuclear ribonucleoprotein A2/B1 isoform B1 (hnRNP A2/B1 isoform B1) and uracil DNA glycosylase (UDG) in hepG2 cells.
Cell Biochem Funct. 2009; 27(4):228-37 [PubMed] Related Publications
Sumoylation is one of the post-translational modifications that governs many cellular activities, including subcellular localization targeting, protein-protein interaction, and transcriptional activity regulation. SUMO E3 ligases are responsible for substrate specificity determination in which PIAS is the largest E3 family that consists of five members in human; they are PIAS1, PIAS3, PIASx alpha, PIASx beta, and PIASy. Several studies showed that all these PIAS genes are highly expressed in testis but only a few reports have discussed their expression pattern in other tissues. Though liver is a multifunctional organ and one would expect to find regulation of cellular functions by sumoylation, the identified sumoylation substrates are scarce and few of them correlate with liver cancer. In this report, we have found that PIASx alpha, PIASx beta, and PIASy are highly expressed in liver as well as testis by tissue distribution studies. We thus aimed to identify any SUMO-1 related proteins in liver cancer cells by two-dimensional gel electrophoresis and mass spectrometry. Two up-regulated proteins, heterogeneous nuclear ribonucleoprotein A2/B1 isoform B1 (hnRNP A2/B1 isoform B1) and uracil DNA glycosylase (UDG), have been identified in the EGFP-SUMO-1 over-expressing HepG2 cells. The up-regulation is suggested to be mediated via changes at the translational level or protection from degradation by western blotting and RT-PCR.

Ehrmann J, Strakova N, Vrzalikova K, et al.
Expression of STATs and their inhibitors SOCS and PIAS in brain tumors. In vitro and in vivo study.
Neoplasma. 2008; 55(6):482-7 [PubMed] Related Publications
Proteins of STAT family belongs to the transcription factors. Through their binding to the DNA specific sites and consequent regulation of transcription of various genes, these signaling proteins play an important role in many cell functions. Recent studies demonstrated persistent activation of STATs and loss of their natural inhibitors SOCS and PIAS in various human cancers. There is also evidence that experimental pharmacologic or genetic modulation of their function mignt by a new approach in anticancer treatment. The aim of this study was in vitro assesment and analysis of expression of STATs, SOCS and PIAS in glioblastoma cell lines undergoing treatment by PPARgamma agonists/antagonists because PPARgamma and STATs are tightly regulated by an overlapping set of nuclear regulatory proteins. We further analysed immunohistochemical expression of these proteins in vivo, with its correlation to grading in various brain tumors. The results of in vitro study showed decreased expression of phosphorylated form of STAT3 and increase of its inhibitors SOCS3 and PIAS3 in glioblastoma cell lines after treatment with IC50 of PPARgamma agonist ciglitazone. In vivo study failed to reveal changes in STAT3 and SOCS3 expression in either low and high grade astrocytomas, however we detect lower expression of STAT2 in low grade astrocytomas when comparing with high grade astrocytomas and lower expression of STAT3 in ependymomas when comparing with anaplastic ones. The results showed existing relationship between STAT and PPARgamma signaling in glial tumors and further suppport expected important role of STATs in regulation of growth and differentiation in these tumors.

Brantley EC, Nabors LB, Gillespie GY, et al.
Loss of protein inhibitors of activated STAT-3 expression in glioblastoma multiforme tumors: implications for STAT-3 activation and gene expression.
Clin Cancer Res. 2008; 14(15):4694-704 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
PURPOSE: STATs activate transcription in response to numerous cytokines, controlling proliferation, gene expression, and apoptosis. Aberrant activation of STAT proteins, particularly STAT-3, is implicated in the pathogenesis of many cancers, including GBM, by promoting cell cycle progression, stimulating angiogenesis, and impairing tumor immune surveillance. Little is known about the endogenous STAT inhibitors, the PIAS proteins, in human malignancies. The objective of this study was to examine the expression of STAT-3 and its negative regulator, PIAS3, in human tissue samples from control and GBM brains.
EXPERIMENTAL DESIGN: Control and GBM human tissues were analyzed by immunoblotting and immunohistochemistry to determine the activation status of STAT-3 and expression of the PIAS3 protein. The functional consequence of PIAS3 inhibition by small interfering RNA or PIAS3 overexpression in GBM cells was determined by examining cell proliferation, STAT-3 transcriptional activity, and STAT-3 target gene expression. This was accomplished using [(3)H]TdR incorporation, STAT-3 dominant-negative constructs, reverse transcription-PCR, and immunoblotting.
RESULTS AND CONCLUSIONS: STAT-3 activation, as assessed by tyrosine and serine phosphorylation, was elevated in GBM tissue compared with control tissue. Interestingly, we observed expression of PIAS3 in control tissue, whereas PIAS3 protein expression in GBM tissue was greatly reduced. Inhibition of PIAS3 resulted in enhanced glioblastoma cellular proliferation. Conversely, PIAS3 overexpression inhibited STAT-3 transcriptional activity, expression of STAT-3-regulated genes, and cell proliferation. We propose that the loss of PIAS3 in GBM contributes to enhanced STAT-3 transcriptional activity and subsequent cell proliferation.

McHale K, Tomaszewski JE, Puthiyaveettil R, et al.
Altered expression of prolactin receptor-associated signaling proteins in human breast carcinoma.
Mod Pathol. 2008; 21(5):565-71 [PubMed] Related Publications
Prolactin receptor signaling can modulate proliferation, survival, motility, angiogenesis, and differentiation in breast cancer. Increased serum prolactin is associated with a significantly increased risk of breast cancer in post-menopausal women. The purpose of this study was to examine the expression of prolactin receptor-associated signaling proteins in breast cancer vs benign breast tissue. Breast tissue microarrays representing 40 cases of benign and malignant pathologies were obtained from the Cooperative Human Tissue Network. Standard immunohistochemistry for prolactin and prolactin receptor-associated proteins was performed. Both positive regulators (c-Myb, Nek3, Vav2) and negative regulators (PIAS3, SIRP) of prolactin receptor signaling were examined. Virtual slides were created from the stained breast tissue microarrays. Labels were scored by region of interest and labeling indices incorporating percent target labeled and label intensity were created. Quantitative determinations of labels were made using the Clarient image system. The unpaired t-test was used to compare labels from benign and malignant tissues. Visual scoring data showed upregulation of Nek3 (P=0.000377), PIAS3 (P=0.000257), and prolactin (P=0.002576) in breast cancer vs normal/hyperplastic epithelium. c-Myb showed a trend toward upregulation, but this did not achieve statistical significance (P=0.107374). SIRP (P=0.002060) was downregulated. Vav2 showed a trend toward downregulation (P=0.107456), but this did not achieve statistical significance. Clarient analysis corroborated upregulation in cancer of Nek3 (P=0.000013), PIAS3 (P=0.000067), and prolactin (P=0.017569). In conclusion, regulators of prolactin receptor signaling show heterogeneity in their expression in benign vs malignant breast tissue. Since these species are known to regulate prolactin-mediated actions, these results suggest multiple targets for modulating prolactin receptor-mediated growth and differentiation in breast cancer.

Roukens MG, Alloul-Ramdhani M, Vertegaal AC, et al.
Identification of a new site of sumoylation on Tel (ETV6) uncovers a PIAS-dependent mode of regulating Tel function.
Mol Cell Biol. 2008; 28(7):2342-57 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
Cell proliferation and differentiation are governed by a finely controlled balance between repression and activation of gene expression. The vertebrate Ets transcriptional repressor Tel (ETV6) and its invertebrate orthologue Yan, play pivotal roles in cell fate determination although the precise mechanisms by which repression of gene expression by these factors is achieved are not clearly defined. Here, we report the identification and characterization of the primary site of sumoylation of Tel, lysine 11 (K11), which is highly conserved in vertebrates (except Danio rerio). We demonstrate that in cells PIAS3 binds to Tel and stimulates sumoylation of K11 in the nucleus. Both Tel monomers and oligomers are efficiently sumoylated on K11 in vitro; but in cells only Tel oligomers are found conjugated with SUMO, whereas sumoylation of Tel monomers is transitory and appears to sensitize them for proteasomal degradation. Mechanistically, sumoylation of K11 inhibits repression of gene expression by full-length Tel. In accordance with this observation, we found that sumoylation impedes Tel association with DNA. By contrast, a Tel isoform lacking K11 (TelM43) is strongly repressive. This isoform results from translation from an alternative initiation codon (M43) that is common to all Tel proteins that also contain the K11 sumoylation consensus site. We find that PIAS3 may have a dual, context-dependent influence on Tel; it mediates Tel sumoylation, but it also augments Tel's repressive function in a sumoylation-independent fashion. Our data support a model that suggests that PIAS-mediated sumoylation of K11 and the emergence of TelM43 in early vertebrates are linked and that this serves to refine spatiotemporal control of gene expression by Tel by establishing a pool of Tel molecules that are available either to be recycled to reinforce repression of gene expression or are degraded in a regulated fashion.

Brayman MJ, Dharmaraj N, Lagow E, Carson DD
MUC1 expression is repressed by protein inhibitor of activated signal transducer and activator of transcription-y.
Mol Endocrinol. 2007; 21(11):2725-37 [PubMed] Related Publications
Mucin 1 (MUC1) is a transmembrane glycoprotein that modulates the interaction between the embryo and the uterine epithelial cell surface. MUC1 also is a tumor marker and has been implicated in the protection of cancer cells from immune cell attack as well as in cell signaling in some tumors. We and others have shown that MUC1 expression is activated by progesterone (P), TNF-alpha, and interferon-gamma (IFN-gamma). Here we demonstrate that MUC1 expression is down-regulated by overexpression of members of the protein inhibitor of activated signal transducer and activator of transcription (PIAS) family, PIAS1, PIAS3, PIASxalpha, PIASxbeta, and PIASy, in human uterine epithelial cell lines HES and HEC-1A and in a breast cancer cell line, T47D. Treatments with P, TNF-alpha, and IFN-gamma were unable to overcome the repression by PIASy. PIASy repression of basal, P-, and TNF-alpha-stimulated MUC1 promoter activity was not dependent on the PIASy sumoylation domain. In contrast, PIASy suppression of IFN-gamma-activated MUC1 promoter activity was dependent on the PIASy sumoylation domain. PIASy and P receptor B were localized to the nucleus upon P treatment, and small interfering RNA knockdown of PIASy resulted in an increase in P-mediated stimulation of MUC1 protein expression. Overexpression of PIASy did not affect P receptor B binding to the MUC1 promoter but surprisingly led to a loss of nuclear receptor corepressor (NCoR), which was recruited to the promoter in response to P. Collectively, these data indicate that PIASy may be a useful target for down-regulation of MUC1 expression in various contexts.

Zhang SJ, Shi JY, Zhu YM, et al.
The investigation of mutation and single nucleotide polymorphism of receptor tyrosine kinases and downstream scaffold molecules in acute myeloid leukemia.
Leuk Lymphoma. 2006; 47(12):2610-6 [PubMed] Related Publications
We investigate the role of mutations of receptor tyrosine kinases as well as their downstream scaffold molecules in leukemogenesis of acute myeloid leukemia (AML) in Chinese patients. Genes of interest included FLT3, PDGFRbeta, KDR, CSF2Rbeta, SOCS1, PIAS3 and SHIP. The coding sequence of these genes was analysed by the reverse transcription-polymerase chain reaction to search novel mutations. A novel mutation (A > T, Q1154L) of SHIP (1 of 192, 0.52%) was identified and another novel mutation (C > T, R685C) of PDGFRbeta (2 of 192, 1.04%). In addition, FLT3 mutations were seen in three of five patients with AML following myelodysplastic syndrome (60%) and 39 of 268 (14.6%) de novo AML patients (P < 0.05). No mutations were found in the coding sequence regions of KDR, CSF2Rbeta, SOCS1 or PIAS3.

Ogata Y, Osaki T, Naka T, et al.
Overexpression of PIAS3 suppresses cell growth and restores the drug sensitivity of human lung cancer cells in association with PI3-K/Akt inactivation.
Neoplasia. 2006; 8(10):817-25 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
Constitutively activated signal transducers and activators of transcription (STAT) are reported to cause uncontrolled transmission of growth signals. In this study, we analyzed the roles of an inhibitor of STAT, protein inhibitor of activated STAT (PIAS) 3, in the development of lung cancer. Treatment with an inhibitor of phosphatidylinositol 3-kinase, LY294002, retarded the growth of human lung cancer cells and rendered them more sensitive to chemotherapeutic agents. However, the inhibition of JAK/STAT by AG490 significantly suppressed cell growth but did not increase drug sensitivity at all. Overexpression of PIAS3 not only significantly inhibited cell growth but also rendered cancer cells up to 12.0-fold more sensitive to the above drugs, which was associated with the suppression of Akt phosphorylation. Inhibition of PIAS3 with small interfering RNA, nevertheless, led cancer cells to accelerate cell proliferation, deteriorate chemosensitivity, and augment Akt phosphorylation. Although the overexpression of suppressors of cytokine signaling 3 in cancer cells also inhibited cell growth and STAT3 phosphorylation, it neither increased sensitivity to chemotherapeutic drugs nor affected the phosphorylation of Akt. These results indicate that PIAS3 may be an attractive candidate for targeting the JAK/STAT and PI3-K/Akt signaling pathways in cancer treatment.

Tatzel J, Poser I, Schroeder J, Bosserhoff AK
Inhibition of melanoma inhibitory activity (MIA) expression in melanoma cells leads to molecular and phenotypic changes.
Pigment Cell Res. 2005; 18(2):92-101 [PubMed] Related Publications
The secreted protein melanoma inhibitory activity (MIA) is highly expressed in malignant melanoma but not in melanocytes and is associated with tumor progression in vivo. Here, we further investigated the functional role of MIA by inhibiting MIA expression of the human melanoma cell line HMB2 via stable antisense MIA cDNA transfection, and subsequent analysis of the cell clones. MIA-deficient cell clones showed several changes in cell morphology and growth pattern. In monolayer and three-dimensional culture enhanced cell-cell contacts were formed. Furthermore, a re-induction of pigment synthesis in comparison with the amelanotic parental cell line HMB2 was observed. Molecular analyses revealed a re-expression of tyrosinase-related protein 1 (Trp-1) and tyrosinase in the MIA-deficient cell clones necessary for melanin synthesis. In accordance, re-expression of MIA in the MIA-deficient melanoma cell clones resulted in downregulation of Trp-1. To identify the molecular mechanisms of MIA regulating pigmentation, MITF and PAX3, two positive regulators of Trp-1 and tyrosinase transcription, and PIAS3, a negative regulator of MITF activity, were analyzed. Only in MIA-deficient cells, expression of PAX3 mRNA and MITF protein was found. In contrast, strong expression of PIAS3 was detected in HMB2 but not in the MIA-deficient cells. To our knowledge this is the first report demonstrating a correlation between MIA expression and pigmentation and morphology of melanocytic cells.

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