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PTMS; parathymosin (12p13)

Gene Summary

Gene:PTMS; parathymosin
Aliases: ParaT
Location:12p13
Summary:-
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:parathymosin
HPRD
Source:NCBI
Updated:15 December, 2014

Gene
Ontology:

What does this gene/protein do?
PTMS is implicated in:
- cytosol
- DNA replication
- nucleus
Data from Gene Ontology via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 15 December 2014 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.

  • Amino Acid Sequence
  • Neoplastic Cell Transformation
  • Transcription Factors
  • Viral Proteins
  • Cancer Gene Expression Regulation
  • Transfection
  • Neoplasm Proteins
  • Up-Regulation
  • Tumor Markers
  • Phenotype
  • Antineoplastic Agents
  • Peptide Fragments
  • Methylation
  • Reproducibility of Results
  • Proteomics
  • Protein Structure, Tertiary
  • Synucleins
  • Models, Molecular
  • Tumor Microenvironment
  • Thyroid Cancer
  • Epigenetics
  • Mass Spectrometry
  • Gene Expression Profiling
  • Hepatocellular Carcinoma
  • Protein Processing, Post-Translational
  • Histones
  • Molecular Sequence Data
  • Protein Isoforms
  • Biological Markers
  • Signal Transduction
  • Acetylation
  • p53 Protein
  • Systems Biology
  • Neoplasm Metastasis
  • Phosphorylation
  • Proteome
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Liver Cancer
  • Chromosome 12
  • Breast Cancer
Tag cloud generated 15 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (3)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerPTMS and Breast Cancer View Publications4
Liver CancerPTMS and Liver Cancer View Publications3
Thyroid CancerPTMS and Thyroid Cancer View Publications2

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

Related Links

Latest Publications: PTMS (cancer-related)

Wetie AG, Woods AG, Darie CC
Mass spectrometric analysis of post-translational modifications (PTMs) and protein-protein interactions (PPIs).
Adv Exp Med Biol. 2014; 806:205-35 [PubMed] Related Publications
Of the 25,000-30,000 human genes, about 2 % code for proteins. However, there are about one to two million protein entities. This is primarily due to alternative splicing and post-translational modifications (PTMs). Identifying all these modifications in one proteome at a particular time point during development or during the transition from normal to cancerous cells is a great challenge to scientists. In addition, identifying the biological significance of all these modifications, as well as their nature, such as stable versus transient modifications, is an even more challenging. Furthermore, interaction of proteins and protein isoforms that have one or more stable or transient PTMs with other proteins and protein isoforms makes the study of proteins daunting and complex. Here we review some of the strategies to study proteins, protein isoforms, protein PTMs, and protein-protein interactions (PPIs). Our goal is to provide a thorough understanding of these proteins and their isoforms, PTMs and PPIs and to shed light on the biological significance of these factors.

Related: Cancer Prevention and Risk Reduction


Guan D, Shao J, Zhao Z, et al.
PTHGRN: unraveling post-translational hierarchical gene regulatory networks using PPI, ChIP-seq and gene expression data.
Nucleic Acids Res. 2014; 42(Web Server issue):W130-6 [PubMed] Related Publications
Interactions among transcriptional factors (TFs), cofactors and other proteins or enzymes can affect transcriptional regulatory capabilities of eukaryotic organisms. Post-translational modifications (PTMs) cooperate with TFs and epigenetic alterations to constitute a hierarchical complexity in transcriptional gene regulation. While clearly implicated in biological processes, our understanding of these complex regulatory mechanisms is still limited and incomplete. Various online software have been proposed for uncovering transcriptional and epigenetic regulatory networks, however, there is a lack of effective web-based software capable of constructing underlying interactive organizations between post-translational and transcriptional regulatory components. Here, we present an open web server, post-translational hierarchical gene regulatory network (PTHGRN) to unravel relationships among PTMs, TFs, epigenetic modifications and gene expression. PTHGRN utilizes a graphical Gaussian model with partial least squares regression-based methodology, and is able to integrate protein-protein interactions, ChIP-seq and gene expression data and to capture essential regulation features behind high-throughput data. The server provides an integrative platform for users to analyze ready-to-use public high-throughput Omics resources or upload their own data for systems biology study. Users can choose various parameters in the method, build network topologies of interests and dissect their associations with biological functions. Application of the software to stem cell and breast cancer demonstrates that it is an effective tool for understanding regulatory mechanisms in biological complex systems. PTHGRN web server is publically available at web site http://www.byanbioinfo.org/pthgrn.

Related: Breast Cancer


Waitkus MS, Chandrasekharan UM, Willard B, et al.
Signal integration and gene induction by a functionally distinct STAT3 phosphoform.
Mol Cell Biol. 2014; 34(10):1800-11 [PubMed] Free Access to Full Article Related Publications
Aberrant activation of the ubiquitous transcription factor STAT3 is a major driver of solid tumor progression and pathological angiogenesis. STAT3 activity is regulated by numerous posttranslational modifications (PTMs), including Tyr(705) phosphorylation, which is widely used as an indicator of canonical STAT3 function. Here, we report a noncanonical mechanism of STAT3 activation that occurs independently of Tyr(705) phosphorylation. Using quantitative liquid chromatography-tandem mass spectrometry, we have discovered and characterized a novel STAT3 phosphoform that is simultaneously phosphorylated at Thr(714) and Ser(727) by glycogen synthase kinase 3α and -β (GSK-3α/β). Both Thr(714) and Ser(727) are required for STAT3-dependent gene induction in response to simultaneous activation of epidermal growth factor receptor (EGFR) and protease-activated receptor 1 (PAR-1) in endothelial cells. In this combinatorial signaling context, preventing formation of doubly phosphorylated STAT3 by depleting GSK-3α/β is sufficient to disrupt signal integration and inhibit STAT3-dependent gene expression. Levels of doubly phosphorylated STAT3 but not of Tyr(705)-phosphorylated STAT3 are remarkably elevated in clear-cell renal-cell carcinoma relative to adjacent normal tissue, suggesting that the GSK-3α/β-STAT3 pathway is active in the disease. Collectively, our results describe a functionally distinct, noncanonical STAT3 phosphoform that positively regulates target gene expression in a combinatorial signaling context and identify GSK-3α/β-STAT3 signaling as a potential therapeutic target in renal-cell carcinoma.

Related: Kidney Cancer Signal Transduction EGFR


Sundar IK, Nevid MZ, Friedman AE, Rahman I
Cigarette smoke induces distinct histone modifications in lung cells: implications for the pathogenesis of COPD and lung cancer.
J Proteome Res. 2014; 13(2):982-96 [PubMed] Article available free on PMC after 07/02/2015 Related Publications
Cigarette smoke (CS)-mediated oxidative stress induces several signaling cascades, including kinases, which results in chromatin modifications (histone acetylation/deacetylation and histone methylation/demethylation). We have previously reported that CS induces chromatin remodeling in pro-inflammatory gene promoters; however, the underlying site-specific histone marks formed in histones H3 and H4 during CS exposure in lungs in vivo and in lung cells in vitro, which can either drive gene expression or repression, are not known. We hypothesize that CS exposure in mouse and human bronchial epithelial cells (H292) can cause site-specific posttranslational histone modifications (PTMs) that may play an important role in the pathogenesis of CS-induced chronic lung diseases. We used a bottom-up mass spectrometry approach to identify some potentially novel histone marks, including acetylation, monomethylation, and dimethylation, in specific lysine and arginine residues of histones H3 and H4 in mouse lungs and H292 cells. We found that CS-induced distinct posttranslational histone modification patterns in histone H3 and histone H4 in lung cells, which may be considered as usable biomarkers for CS-induced chronic lung diseases. These identified histone marks (histone H3 and histone H4) may play an important role in the epigenetic state during the pathogenesis of smoking-induced chronic lung diseases, such as chronic obstructive pulmonary disease and lung cancer.

Related: Lung Cancer


Hitosugi T, Chen J
Post-translational modifications and the Warburg effect.
Oncogene. 2014; 33(34):4279-85 [PubMed] Related Publications
Post-translational modification (PTM) is an important step of signal transduction that transfers chemical groups such as phosphate, acetyl and glycosyl groups from one protein to another protein. As most of the PTMs are reversible, normal cells use PTMs as a 'switch' to determine the resting and proliferating state of cells that enables rapid and tight regulation of cell proliferation. In cancer cells, activation of oncogenes and/or inactivation of tumor suppressor genes provide continuous proliferative signals in part by adjusting the state of diverse PTMs of effector proteins that are involved in regulation of cell survival, cell cycle and proliferation, leading to abnormally fast proliferation of cancer cells. In addition to dysregulated proliferation, 'altered tumor metabolism' has recently been recognized as an emerging cancer hallmark. The most common metabolic phenotype of cancer is known as the Warburg effect or aerobic glycolysis that consists of increased glycolysis and enhanced lactate production even in the presence of oxygen. Although Otto Warburg observed aerobic glycolysis nearly 90 years ago, the detailed molecular mechanisms how increased glycolysis is regulated by oncogenic and/or tumor suppressive signaling pathways remain unclear. In this review, we summarize recent advances revealing how these signaling pathways reprogram metabolism through diverse PTMs to provide a metabolic advantage to cancer cells, thereby promoting tumor cell proliferation, tumorigenesis and tumor growth.

Related: Cancer Prevention and Risk Reduction


Thompson LL, Guppy BJ, Sawchuk L, et al.
Regulation of chromatin structure via histone post-translational modification and the link to carcinogenesis.
Cancer Metastasis Rev. 2013; 32(3-4):363-76 [PubMed] Related Publications
The loss of genome integrity contributes to the development of tumors. Although genome instability is associated with virtually all tumor types including both solid and liquid tumors, the aberrant molecular origins that drive this instability are poorly understood. It is now becoming clear that epigenetics and specific histone post-translational modifications (PTMs) have essential roles in maintaining genome stability under normal conditions. A strong relationship exists between aberrant histone PTMs, genome instability, and tumorigenesis. Changes in the genomic location of specific histone PTMs or alterations in the steady-state levels of the PTM are the consequence of imbalances in the enzymes and their activities catalyzing the addition of PTMs ("writers") or removal of PTMs ("erasers"). This review focuses on the misregulation of three specific types of histone PTMs: histone H3 phosphorylation at serines 10 and 28, H4 mono-methylation at lysine 20, and H2B ubiquitination at lysine 120. We discuss the normal regulation of these PTMs by the respective "writers" and "erasers" and the impact of their misregulation on genome stability.

Related: Cancer Prevention and Risk Reduction


Uen YH, Lin KY, Sun DP, et al.
Comparative proteomics, network analysis and post-translational modification identification reveal differential profiles of plasma Con A-bound glycoprotein biomarkers in gastric cancer.
J Proteomics. 2013; 83:197-213 [PubMed] Related Publications
UNLABELLED: In the study, we used Con A affinity chromatography, 1-D gel electrophoresis, and nano-LC-MS/MS to screen biomarker candidates in plasma samples obtained from 30 patients with gastric cancer and 30 healthy volunteers. First, we pooled plasma samples matched by age and sex. We identified 17 differentially expressed Con A-bound glycoproteins, including 10 upregulated proteins and 7 downregulated proteins; these differences were significant (Student's t-test, p-value<0.05). Furthermore, 2 of the upregulated proteins displayed expression levels that were increased by 2-fold or more in gastric cancer samples when compared with normal control samples. These proteins included leucine-rich alpha-2-glycoprotein (LRG1) and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), and the expression levels were validated by Western blot analysis. Pathway and network analysis of the differentially expressed proteins by Ingenuity Pathway Analysis revealed vital canonical pathways involving acute phase response signaling, the complement system, LXR/RXR activation, hematopoiesis from pluripotent stem cells, and primary immunodeficiency signaling. Our results suggest that Con A-bound LRG1 and ITIH3 may not be practically applicable as a robust biomarker for the early detection of gastric cancer. Additionally, three novel PTMs in ITIH3 were identified and include hexose-N-acetyl-hexosamine at asparagine-(41), trimethylation at aspartic acid-(290), and flavin adenine dinucleotide at histidine-(335).
BIOLOGICAL SIGNIFICANCE: Our study was to describe a combinatorial approach of Con A affinity chromatography, 1-D SDS-PAGE, and nano-LC/MS/MS that provides a label-free, comparative glycoproteomic quantification strategy for the investigation of glycoprotein profiles in plasma from gastric cancer patients versus healthy volunteers and to identify glycoprotein biomarkers for the early clinical detection of gastric cancer. Three novel PTMs, HexHexNAc, trimethylation and FAD, in Con A-bound ITIH3 were identified and built in molecular modeling. The aspartic acid-(290) trimethylation site was located in a metal ion-dependent adhesion site (MIDAS motif; (290)-DXSXS…T…D-(313)) that may influence important function for binding protein ligands.

Related: Stomach Cancer Gastric Cancer


Collins HM, Abdelghany MK, Messmer M, et al.
Differential effects of garcinol and curcumin on histone and p53 modifications in tumour cells.
BMC Cancer. 2013; 13:37 [PubMed] Article available free on PMC after 07/02/2015 Related Publications
BACKGROUND: Post-translational modifications (PTMs) of histones and other proteins are perturbed in tumours. For example, reduced levels of acetylated H4K16 and trimethylated H4K20 are associated with high tumour grade and poor survival in breast cancer. Drug-like molecules that can reprogram selected histone PTMs in tumour cells are therefore of interest as potential cancer chemopreventive agents. In this study we assessed the effects of the phytocompounds garcinol and curcumin on histone and p53 modification in cancer cells, focussing on the breast tumour cell line MCF7.
METHODS: Cell viability/proliferation assays, cell cycle analysis by flow cytometry, immunodetection of specific histone and p53 acetylation marks, western blotting, siRNA and RT-qPCR.
RESULTS: Although treatment with curcumin, garcinol or the garcinol derivative LTK-14 hampered MCF7 cell proliferation, differential effects of these compounds on histone modifications were observed. Garcinol treatment resulted in a strong reduction in H3K18 acetylation, which is required for S phase progression. Similar effects of garcinol on H3K18 acetylation were observed in the osteosarcoma cells lines U2OS and SaOS2. In contrast, global levels of acetylated H4K16 and trimethylated H4K20 in MCF7 cells were elevated after garcinol treatment. This was accompanied by upregulation of DNA damage signalling markers such as γH2A.X, H3K56Ac, p53 and TIP60. In contrast, exposure of MCF7 cells to curcumin resulted in increased global levels of acetylated H3K18 and H4K16, and was less effective in inducing DNA damage markers. In addition to its effects on histone modifications, garcinol was found to block CBP/p300-mediated acetylation of the C-terminal activation domain of p53, but resulted in enhanced acetylation of p53K120, and accumulation of p53 in the cytoplasmic compartment. Finally, we show that the elevation of H4K20Me3 levels by garcinol correlated with increased expression of SUV420H2, and was prevented by siRNA targeting of SUV420H2.
CONCLUSION: In summary, although garcinol and curcumin can both inhibit histone acetyltransferase activities, our results show that these compounds have differential effects on cancer cells in culture. Garcinol treatment alters expression of chromatin modifying enzymes in MCF7 cells, resulting in reprogramming of key histone and p53 PTMs and growth arrest, underscoring its potential as a cancer chemopreventive agent.

Related: Breast Cancer TP53


Shiromizu T, Adachi J, Watanabe S, et al.
Identification of missing proteins in the neXtProt database and unregistered phosphopeptides in the PhosphoSitePlus database as part of the Chromosome-centric Human Proteome Project.
J Proteome Res. 2013; 12(6):2414-21 [PubMed] Related Publications
The Chromosome-Centric Human Proteome Project (C-HPP) is an international effort for creating an annotated proteomic catalog for each chromosome. The first step of the C-HPP project is to find evidence of expression of all proteins encoded on each chromosome. C-HPP also prioritizes particular protein subsets, such as those with post-translational modifications (PTMs) and those found in low abundance. As participants in C-HPP, we integrated proteomic and phosphoproteomic analysis results from chromosome-independent biomarker discovery research to create a chromosome-based list of proteins and phosphorylation sites. Data were integrated from five independent colorectal cancer (CRC) samples (three types of clinical tissue and two types of cell lines) and lead to the identification of 11,278 proteins, including 8,305 phosphoproteins and 28,205 phosphorylation sites; all of these were categorized on a chromosome-by-chromosome basis. In total, 3,033 "missing proteins", i.e., proteins that currently lack evidence by mass spectrometry, in the neXtProt database and 12,852 unknown phosphorylation sites not registered in the PhosphoSitePlus database were identified. Our in-depth phosphoproteomic study represents a significant contribution to C-HPP. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium with the data set identifier PXD000089.

Related: Colorectal (Bowel) Cancer


Surguchov A
Synucleins: are they two-edged swords?
J Neurosci Res. 2013; 91(2):161-6 [PubMed] Related Publications
The synuclein family consists of three distinct highly homologous genes, α-synuclein, β-synuclein, and γ-synuclein, which have so far been found only in vertebrates. Proteins encoded by these genes are characterized by an acidic C-terminal region and five or six imperfect repeat motifs (KTKEGV) distributed throughout the highly conserved N-terminal region. Numerous data demonstrate that synucleins are implicated in two groups of the most devastating human disorders, i.e., neurodegenerative diseases (NDDs) and cancer. Mutations in the α-synuclein gene are associated with familial forms of Parkinson's disease (PD), and accumulation of α-synuclein inclusions is a hallmark of this disorder. In breast cancer, increased expression of γ-synuclein correlates with disease progression. Conversely, some results indicate that the members of the synuclein family may have a protective effect. How might these small proteins combine such controversial properties? We present evidence that synuclein's features are basically regulated by two mechanisms, i.e., posttranslational modifications (PTMs) and the level of their expression. We also discuss a new, emerging area of investigation of synucleins, namely, their role in the cell-to-cell propagation of pathology.

Related: Cancer Prevention and Risk Reduction


Wang CM, Brennan VC, Gutierrez NM, et al.
SUMOylation of ATF3 alters its transcriptional activity on regulation of TP53 gene.
J Cell Biochem. 2013; 114(3):589-98 [PubMed] Related Publications
Cyclic AMP-dependent transcription factor-3 (ATF3), a stress sensor, plays an essential role in cells to maintain homeostasis and has diverse functions in cellular survival and death signal pathways. ATF3 is a novel regulator of p53 protein stability and function. The activities of ATF3 are modulated by post-translational modifications (PTMs), such as ubiquitination, but whether it is modified by small ubiquitin-related modifier (SUMO) remains unknown. The aim of this study was to investigate whether ATF3 is post-translationally modified by SUMO proteins and also to elucidate SUMOylation of ATF3 on TP53 gene activity. Here we report that ATF3 is clearly defined as a SUMO target protein both in vitro SUMOylation assay using recombinant proteins and at the cellular levels. Furthermore, ATF3 interacted with UBE2I, the only SUMO E2 enzyme found so far. In addition, PIAS3β (a SUMO E3 ligase) enhanced and SENP2 and SENP7 (two SUMOylation proteases) decreased SUMOylation of ATF3, respectively. Finally, we found that ATF3 is selectively SUMOylated at lysine residue 42 but the SUMOylation does not alter subcellular localization of ATF3. We then characterized the functional role of ATF3 SUMOylation on TP53 gene expression. We found that SUMOylation of ATF3 is required for full repression of TP53 gene. Overall, we provide the first evidence that ATF3 is post-translationally modified by SUMO and SUMOylation of ATF3 plays a functional role in regulation of TP53 gene activity.

Related: Cancer Prevention and Risk Reduction TP53


Cozzolino AM, Alonzi T, Santangelo L, et al.
TGFβ overrides HNF4α tumor suppressing activity through GSK3β inactivation: implication for hepatocellular carcinoma gene therapy.
J Hepatol. 2013; 58(1):65-72 [PubMed] Related Publications
BACKGROUND & AIMS: The tumor fate derives from cell autonomous properties and niche microenvironmental cues. The transforming growth factor β (TGFβ) is a major microenvironmental factor for hepatocellular carcinoma (HCC) influencing tumor dedifferentiation, induction of epithelial-to-mesenchymal transition (EMT) and acquisition of metastatic properties. The loss of the transcriptional factor HNF4α is a predominant mechanism through which HCCs progress to a more aggressive phenotype; its re-expression, reducing tumor formation and repressing EMT program, has been suggested as a therapeutic tool for HCC gene therapy. We investigated the influence of TGFβ on the anti-EMT and tumor suppressor HNF4α activity.
METHODS: Cell motility and invasion were analyzed by wound healing and invasion assays. EMT was evaluated by RT-qPCR and immunofluorescence. ChIP and EMSA assays were utilized for investigation of the HNF4α DNA binding activity. HNF4α post-translational modifications (PTMs) were assessed by 2-DE analysis. GSK3β activity was modulated by chemical inhibition and constitutive active mutant expression.
RESULTS: We demonstrated that the presence of TGFβ impairs the efficiency of HNF4α as tumor suppressor. We found that TGFβ induces HNF4α PTMs that correlate with the early loss of HNF4α DNA binding activity on target gene promoters. Furthermore, we identified the GSK3β kinase as one of the TGFβ targets mediating HNF4α functional inactivation: GSK3β chemical inhibition results in HNF4α DNA binding impairment while a constitutively active GSK3β mutant impairs the TGFβ-induced inhibitory effect on HNF4α tumor suppressor activity.
CONCLUSIONS: Our data identify in the dominance of TGFβ a limit for the HNF4α-mediated gene therapy of HCC.

Related: Liver Cancer


Peters AA, Simpson PT, Bassett JJ, et al.
Calcium channel TRPV6 as a potential therapeutic target in estrogen receptor-negative breast cancer.
Mol Cancer Ther. 2012; 11(10):2158-68 [PubMed] Related Publications
Calcium signaling is a critical regulator of cell proliferation. Elevated expression of calcium channels and pumps is a characteristic of some cancers, including breast cancer. We show that the plasma membrane calcium channel TRPV6, which is highly selective for Ca(2+), is overexpressed in some breast cancer cell lines. Silencing of TRPV6 expression in a breast cancer cell line with increased endogenous TRPV6 expression leads to a reduction in basal calcium influx and cellular proliferation associated with a reduction in DNA synthesis. TRPV6 gene amplification was identified as one mechanism of TRPV6 overexpression in a subset of breast cancer cell lines and breast tumor samples. Analysis of two independent microarray expression datasets from breast tumor samples showed that increased TRPV6 expression is a feature of estrogen receptor (ER)-negative breast tumors encompassing the basal-like molecular subtype, as well as HER2-positive tumors. Breast cancer patients with high TRPV6 levels had decreased survival compared with patients with low or intermediate TRPV6 expression. Our findings suggest that inhibitors of TRPV6 may offer a novel therapeutic strategy for the treatment of ER-negative breast cancers.

Related: Breast Cancer


Davis FM, Peters AA, Grice DM, et al.
Non-stimulated, agonist-stimulated and store-operated Ca2+ influx in MDA-MB-468 breast cancer cells and the effect of EGF-induced EMT on calcium entry.
PLoS One. 2012; 7(5):e36923 [PubMed] Article available free on PMC after 07/02/2015 Related Publications
In addition to their well-defined roles in replenishing depleted endoplasmic reticulum (ER) Ca(2+) reserves, molecular components of the store-operated Ca(2+) entry pathway regulate breast cancer metastasis. A process implicated in cancer metastasis that describes the conversion to a more invasive phenotype is epithelial-mesenchymal transition (EMT). In this study we show that EGF-induced EMT in MDA-MB-468 breast cancer cells is associated with a reduction in agonist-stimulated and store-operated Ca(2+) influx, and that MDA-MB-468 cells prior to EMT induction have a high level of non-stimulated Ca(2+) influx. The potential roles for specific Ca(2+) channels in these pathways were assessed by siRNA-mediated silencing of ORAI1 and transient receptor potential canonical type 1 (TRPC1) channels in MDA-MB-468 breast cancer cells. Non-stimulated, agonist-stimulated and store-operated Ca(2+) influx were significantly inhibited with ORAI1 silencing. TRPC1 knockdown attenuated non-stimulated Ca(2+) influx in a manner dependent on Ca(2+) influx via ORAI1. TRPC1 silencing was also associated with reduced ERK1/2 phosphorylation and changes in the rate of Ca(2+) release from the ER associated with the inhibition of the sarco/endoplasmic reticulum Ca(2+)-ATPase (time to peak [Ca(2+)](CYT) = 188.7 ± 34.6 s (TRPC1 siRNA) versus 124.0 ± 9.5 s (non-targeting siRNA); P<0.05). These studies indicate that EMT in MDA-MB-468 breast cancer cells is associated with a pronounced remodeling of Ca(2+) influx, which may be due to altered ORAI1 and/or TRPC1 channel function. Our findings also suggest that TRPC1 channels in MDA-MB-468 cells contribute to ORAI1-mediated Ca(2+) influx in non-stimulated cells.

Related: Breast Cancer


Anbalagan M, Huderson B, Murphy L, Rowan BG
Post-translational modifications of nuclear receptors and human disease.
Nucl Recept Signal. 2012; 10:e001 [PubMed] Article available free on PMC after 07/02/2015 Related Publications
Nuclear receptors (NR) impact a myriad of physiological processes including homeostasis, reproduction, development, and metabolism. NRs are regulated by post-translational modifications (PTM) that markedly impact receptor function. Recent studies have identified NR PTMs that are involved in the onset and progression of human diseases, including cancer. The majority of evidence linking NR PTMs with disease has been demonstrated for phosphorylation, acetylation and sumoylation of androgen receptor (AR), estrogen receptor α (ERα), glucocorticoid receptor (GR) and peroxisome proliferator activated receptor γ (PPARγ). Phosphorylation of AR has been associated with hormone refractory prostate cancer and decreased disease-specific survival. AR acetylation and sumoylation increased growth of prostate cancer tumor models. AR phosphorylation reduced the toxicity of the expanded polyglutamine AR in Kennedy's Disease as a consequence of reduced ligand binding. A comprehensive evaluation of ERα phosphorylation in breast cancer revealed several sites associated with better clinical outcome to tamoxifen therapy, whereas other phosphorylation sites were associated with poorer clinical outcome. ERα acetylation and sumoylation may also have predictive value for breast cancer. GR phosphorylation and acetylation impact GR responsiveness to glucocorticoids that are used as anti-inflammatory drugs. PPARγ phosphorylation can regulate the balance between growth and differentiation in adipose tissue that is linked to obesity and insulin resistance. Sumoylation of PPARγ is linked to repression of inflammatory genes important in patients with inflammatory diseases. NR PTMs provide an additional measure of NR function that can be used as both biomarkers of disease progression, and predictive markers for patient response to NR-directed treatments.

Related: Breast Cancer PPARG gene Prostate Cancer


Weber GL, Parat MO, Binder ZA, et al.
Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells.
Oncotarget. 2011; 2(11):833-49 [PubMed] Article available free on PMC after 07/02/2015 Related Publications
Glioblastoma multiforme (GBM) is a highly invasive and deadly brain tumor. Tumor cell invasion makes complete surgical resection impossible and reduces the efficacy of other therapies. Genome-wide analyses of mutations, copy-number changes, and expression patterns have provided new insights into genetic abnormalities common in GBM. We analyzed published data and identified the invasion and motility pathways most frequently altered in GBM. These were most notably the focal adhesion and integrin signaling, and extracellular matrix interactions pathways. We mapped alterations in each of these pathways and found that they included the catalytic PIK3CA and regulatory PIK3R1 subunit genes of the class IA PI3K. Knockdown of either of these genes separately in GBM cell lines by lentiviral-mediated shRNA expression resulted in decreased proliferation, migration, and invasion in all lines tested. FAK activity was reduced by knockdown of either PIK3CA or PIK3R1, and MMP2 levels were reduced by knockdown of PIK3R1. We conclude that PIK3R1, like PIK3CA, is a potential therapeutic target in GBM and that it also influences tumor cell growth and motility.


Kim HY, Park WY, Lee KE, et al.
Comparative analysis of gene expression profiles of papillary thyroid microcarcinoma and papillary thyroid carcinoma.
J Cancer Res Ther. 2010 Oct-Dec; 6(4):452-7 [PubMed] Related Publications
PURPOSE: Papillary thyroid carcinomas (PTCs) measuring 1.0 cm or less were separately defined as papillary thyroid microcarcinomas (PTMs) by the World Health Organization, emphasizing on their benign behavior. However, some reported that PTMs may have aggressive behavior, can cause regional, or even distant metastases. But till now, the characteristics of PTMs were only reviewed and described by the clinicopathological parameters, and no analysis of PTM by the gene level is available. We report on the gene expression profiles of PTMs by the oligonucleotide microarrays and the results of comparative analysis with those of PTCs.
MATERIALS AND METHODS: The gene expression profiles of 25 pairs of PTMs and their normal thyroid tissue counterparts, and 11 pairs of PTCs and their normal counterparts, were analyzed by Affymetrix Human Genome U133A. Data were analyzed by the SAM and the DAVID 2008 program to detect differentially expressed genes in supervised sample classification.
RESULTS: Two-hundred thirteen statistically significant up-regulated genes and -183 significant down-regulated genes of PTMs compared with their normal counterpart thyroid tissues, which were mainly cell adhesion-related genes and immune response genes, were detected. Two-hundred sixty-one up-regulated and -157 down-regulated genes of PTCs were also detected. In the comparative analyses of gene expression profiles of PTMs and PTCs, no significant difference was found.
CONCLUSION: PTM should not be considered as the simple occult indolent thyroid cancer, but as the earlier stage of disease which eventually evolves into PTC, because the gene expression profiles of PTMs were not different from those of PTCs.

Related: Thyroid Cancer


Shen F, Kirmani KZ, Xiao Z, et al.
Nuclear protein isoforms: implications for cancer diagnosis and therapy.
J Cell Biochem. 2011; 112(3):756-60 [PubMed] Article available free on PMC after 07/02/2015 Related Publications
Post-translational modifications (PTMs) of nuclear proteins play essential roles in the regulation of gene transcription and signal transduction pathways. Numerous studies have demonstrated a correlation between specific nuclear protein isoforms and cellular malignant process. This communication reviews the impact of major PTM events such as phosphorylation, acetylation, methylation, ubiquitination, and sumoylation on several important nuclear proteins including p53, histones, proliferating cellular nuclear antigen (PCNA), and retinoblastoma protein (Rb) in the process. In addition, the implications of the PTMs as cancer biomarkers and therapeutic targets are considered.

Related: Cancer Prevention and Risk Reduction RB1 TP53 CREB1 gene


York B, Yu C, Sagen JV, et al.
Reprogramming the posttranslational code of SRC-3 confers a switch in mammalian systems biology.
Proc Natl Acad Sci U S A. 2010; 107(24):11122-7 [PubMed] Article available free on PMC after 07/02/2015 Related Publications
Here we demonstrate that reprogramming steroid receptor coactivator-3 (SRC-3) function by changing its posttranslational modification (PTM) code drastically influences systems biology. These findings support the physiological importance of PTMs in directing in vivo functions of a master coregulator. We previously reported that the transactivation potential of SRC-3 is controlled in part by PTMs, although this data emanated from in vitro studies. To test the physiological implications of PTMs on SRC-3, we developed a knock-in mouse model containing mutations at four conserved phosphorylation sites. These mice displayed a systems biology phenotype with increased body weight and adiposity, coupled with reduced peripheral insulin sensitivity. Collectively, these phenotypes result from increased IGF1 signaling, due to elevated IGFBP3 levels. We provide convincing evidence that these mutations in SRC-3 promoted enhanced transcription of the IGFBP3 gene and globally influenced growth and metabolism. Consequently, these mice displayed increased liver tumorigenesis, which likely results from elevated IGF1 signaling.

Related: IGF1 Signal Transduction


Di Michele M, Marcone S, Cicchillitti L, et al.
Glycoproteomics of paclitaxel resistance in human epithelial ovarian cancer cell lines: towards the identification of putative biomarkers.
J Proteomics. 2010; 73(5):879-98 [PubMed] Related Publications
Glycosylation, one of the most common post translational modifications (PTMs) of proteins, is often associated with carcinogenesis and tumor malignancy. Ovarian cancer is the sixth cause of cancer-related death in Western countries. Currently, it is treated by debulking surgery followed by chemotherapy based on paclitaxel, alone or in combination with other drugs. However, chemoresistance represents a major obstacle to positive clinical outcome. We used two approaches, Multiplexed Proteomics (MP) technology and Multilectin Affinity Chromatography (MAC) to characterize the glycoproteome of the human ovarian cancer cell line A2780 and its paclitaxel resistant counterpart A2780TC1. Furthermore proteins were separated by traditional 2DE or DIGE and identified by MS (MALDI TOF or LC MS/MS). Seventy glycoproteins were successfully identified in ovarian cancer cells and 10 were found to be differentially expressed between sensitive and resistant cell lines. We focused on four glycoproteins (tumor rejection antigen (gp96) 1, triose phosphate isomerase, palmitoyl-protein thioesterase 1 precursor and ER-associated DNAJ) which were remarkably upregulated in A2780TC1 compared to A2780 cell line and which may represent biomarkers for paclitaxel resistance in ovarian cancer.

Related: Ovarian Cancer Paclitaxel


Su X, Lucas DM, Zhang L, et al.
Validation of an LC-MS based approach for profiling histones in chronic lymphocytic leukemia.
Proteomics. 2009; 9(5):1197-206 [PubMed] Article available free on PMC after 07/02/2015 Related Publications
The in vitro evaluation of histones and their PTMs has drawn substantial interest in the development of epigenetic therapies. The differential expression of histone isoforms may serve as a potential marker in the classification of diseases affected by chromatin abnormalities. In this study, protein profiling by LC and MS was used to explore differences in histone composition in primary chronic lymphocytic leukemia (CLL) cells. Extensive method validations were performed to determine the experimental variances that would impact histone relative abundance. The resulting data demonstrated that the proposed methodology was suitable for the analysis of histone profiles. In 4 normal individuals and 40 CLL patients, a significant decrease in the relative abundance of histone H2A variants (H2AFL and H2AFA/M*) was observed in primary CLL cells as compared to normal B cells. Protein identities were determined using high mass accuracy MS and shotgun proteomics.

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology


Fan HZ, Liu H, Zhang C, et al.
Comparative proteomics and molecular mechanical analysis in CDA-II induced therapy of LCI-D20 hepatocellular carcinoma model.
J Cancer Res Clin Oncol. 2009; 135(4):591-602 [PubMed] Related Publications
PURPOSE: To investigate the differential proteins and related molecular mechanism of CDA-II (cell differentiation agent-II) induced therapy on a human hepatocellular carcinoma model in nude mice with high metastatic potential (LCI-D20).
METHODS: After tumors were transplanted 11 days, mice were intraperitoneally injected with CDA-II (1,800 mg/kg) for 20 days continuously. The tumor growth-inhibitory efficiency in CDA-II treated groups was calculated. Proteins extracted from tumor tissue were separated by two-dimensional gel electrophoresis (2DE) and the differential proteins were identified by matrix assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS). Western blotting (WB) was performed to verify the expression of certain candidate proteins. Reverse transcription-polymerase chain reaction (RT-PCR) was engaged to study the molecular mechanism of the therapy.
RESULTS: CDA-II suppressed the growth and metastasis of tumor. The tumor growth-inhibitory efficiency was 41.8%. In total, 27 differentially expressed proteins were identified, including HSP27, UGDH, CK8, Hsp60, ENOA and AnxA5, with functions involved in oncogene expression and/or cell differentiation. In addition, apparent alternations of HSP60 and beta-actin expression levels and their different posttranslational modifications (PTMs) were investigated. RT-PCR analysis confirmed that the cancer related genes c-myc, N-ras and MMP-9 were significantly down-regulated.
CONCLUSION: Our results demonstrate that CDA-II presence can change the proteome profiling and favors of the tumor suppression in LCI-D20 cell differentiation. Our results also suggest that the dynamic PTM of HSP60 expression levels could be used to predict HCC and might be a promising and useful biomarker to prognosticate CDA-II therapeutic efficacy.

Related: Liver Cancer MMP9: matrix metallopeptidase 9


Jiang X, Wang Y
Acetylation and phosphorylation of high-mobility group A1 proteins in PC-3 human tumor cells.
Biochemistry. 2006; 45(23):7194-201 [PubMed] Related Publications
In this paper, we examined the posttranslational modifications (PTMs) of high-mobility group A1 (HMGA1) proteins in PC-3 human prostate cancer cells that are either treated or not treated with a histone deacetylase inhibitor, sodium butyrate. We found that, from a reversed-phase C4 column, the HMGA1a protein eluted in two different fractions with distinct forms of PTMs: Ser98, Ser101, and Ser102 were phosphorylated and Arg25 was methylated for both fractions; only the minor fraction, however, is hyperphosphorylated where Ser35, Thr52, and Thr77 were also phosphorylated. In addition, Lys14 was acetylated in the major but not the minor HMGA1a fraction isolated from the PC-3 cells that were not treated with butyrate. Likewise, HMGA1b, which is a splicing variant of HMGA1a, was acetylated on Lys14 and phosphorylated on the corresponding residues, i.e., Thr41, Thr66, Ser87, Ser90, and Ser91. The acetylation and phosphorylation of the HMGA1a and HMGA1b proteins may affect their interactions with other protein factors, which in turn may modulate the binding of HMGA1 proteins to DNA and regulate gene expression. In addition, the specifically posttranslationally modified HMGA1 proteins may serve as molecular biomarkers for cancer diagnosis and prognosis.

Related: Prostate Cancer


Diana F, Di Bernardo J, Sgarra R, et al.
Differential HMGA expression and post-translational modifications in prostatic tumor cells.
Int J Oncol. 2005; 26(2):515-20 [PubMed] Related Publications
The HMGA architectural nuclear factors are involved in chromatin dynamics and their overexpression has been strongly linked to the neoplastic transformation process. Here we investigate the expression and post-translational modifications (PTMs) of HMGA proteins (HMGA1a, HMGA1b and HMGA2) in the rat prostatic cancer Dunning model (G, AT-1, and MAT-Ly-Lu cell lines). We demonstrate the expression of HMGA2, in addition to HMGA1a and HMGA1b, in both the anaplastic cell lines AT-1 and MAT-Ly-Lu and an extremely specific HMGA1a mono-methylation only in the most metastatic cell line MAT-Ly-Lu. The HMGA ectopic expression in HMGA-negative Dunning G cells does not significantly alter their growth ability, suggesting that, although HMGA expression is necessary for the progression of neoplastic transformation in several cellular models, in these cells it is not sufficient. These data suggest exploring HMGA2 as a potential marker in human prostate tumor and moreover indicate PTMs as an additional tool in the staging of tumor progression.

Related: Prostate Cancer


Edberg DD, Bruce JE, Siems WF, Reeves R
In vivo posttranslational modifications of the high mobility group A1a proteins in breast cancer cells of differing metastatic potential.
Biochemistry. 2004; 43(36):11500-15 [PubMed] Related Publications
The high mobility group (HMG) proteins are important modulators of chromatin structure and gene transcription. Overexpression of HMGA1 proteins in vivo induces neoplastic transformation and promotes a highly metastatic cellular phenotype. This study focuses on characterization of HMGA1a in vivo posttranslational modification (PTM) patterns found in a nonmetastatic and two metastatic lines of MCF-7 human breast cancer cells of differing tumorigenic potential. PTM types and the amino acids on which they occur were identified by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. Mass analysis was restricted to MALDI peaks having less than +/-150 parts per million (ppm) error, thereby holding our analysis to a more stringent criterion than previously published work with the HMG proteins. Validation of MALDI-TOF MS analysis was accomplished utilizing electrospray ionization tandem mass spectrometry (ESI MS/MS) and manual analysis of ion fragmentation spectra. Patterns and sites of PTMs identified in this study suggest that HMGA1a proteins, like the histones, exhibit a biochemical modification "code" that relates to cellular function. For example, both increased levels of acetylation and a previously unidentified dimethylation of both lysine and arginine residues were found on HMGA1a proteins from metastatic cells compared to proteins found in their nonmetastatic precursors. Additionally, the types of modification present on lysine-45 (e.g., unmodified, acetylation, or dimethylation) varied, depending on the metastatic potential of cells. These findings suggest that examination of the PTM patterns on HMGA1 proteins may provide valuable information concerning the physiological and phenotypic state of mammalian cells.

Related: Breast Cancer


Journet A, Ferro M
The potentials of MS-based subproteomic approaches in medical science: the case of lysosomes and breast cancer.
Mass Spectrom Rev. 2004 Nov-Dec; 23(6):393-442 [PubMed] Related Publications
Because of the great number of women who are diagnosed with breast cancer each year, and though this disease presents the lowest mortality rate among cancers, breast cancer remains a major public health problem. As for any cancer, the tumorigenic and metastatic processes are still hardly understood, and the biochemical markers that allow either a precise monitoring of the disease or the classification of the numerous forms of breast cancer remain too scarce. Therefore, great hopes are put on the development of high-throughput genomic and proteomic technologies. Such comprehensive techniques should help in understanding the processes and in defining steps of the disease by depicting specific genes or protein profiles. Because techniques dedicated to the current proteomic challenges are continuously improving, the probability of the discovery of new potential protein biomarkers is rapidly increasing. In addition, the identification of such markers should be eased by lowering the sample complexity; e.g., by sample fractionation, either according to specific physico-chemical properties of the proteins, or by focusing on definite subcellular compartments. In particular, proteins of the lysosomal compartment have been shown to be prone to alterations in their localization, expression, or post-translational modifications (PTMs) during the cancer process. Some of them, such as the aspartic protease cathepsin D (CatD), have even been proven as participating actively in the disease progression. The present review aims at giving an overview of the implication of the lysosome in breast cancer, and at showing how subproteomics and the constantly refining MS-based proteomic techniques may help in making breast cancer research progress, and thus, hopefully, in improving disease treatment.

Related: Breast Cancer


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Cite this page: Cotterill SJ. PTMS, Cancer Genetics Web: http://www.cancerindex.org/geneweb/PTMS.htm Accessed: date

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