SPRR2C

Gene Summary


HPRD
Gene:SPRR2C; small proline-rich protein 2C (pseudogene)
Location:1q21-q22
Summary:-
Databases:OMIM, HGNC, GeneCard, Gene
Source:NCBIAccessed: 25 June, 2015

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 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
  • Autologous Transplantat
  • Disease Progression
  • Protein Biosynthesis
  • Neoplasm Invasiveness
  • Chromosome 1
  • Transcriptional Activation
  • Cornified Envelope Proline-Rich Proteins
  • Cell Line
  • Base Sequence
  • Tumor Markers
  • RTPCR
  • Western Blotting
  • Polymerase Chain Reaction
  • Transfection
  • Molecular Sequence Data
  • DNA-Binding Proteins
  • Protein Precursors
  • Messenger RNA
  • Immunohistochemistry
  • Gene Expression Regulation
  • Mutation
  • Cancer Gene Expression Regulation
  • Neoplastic Cell Transformation
  • Lung Cancer
  • Epithelium
  • Gene Expression
  • Skin Cancer
  • Promoter Regions
  • Proteins
  • Membrane Proteins
  • Esophageal Cancer
  • Cell Differentiation
  • Adenocarcinoma
  • Tetradecanoylphorbol Acetate
  • Epithelial Cells
  • Mouth Mucosa
  • Squamous Cell Carcinoma
  • Up-Regulation
  • Keratinocytes
Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: SPRR2C (cancer-related)

Heikinheimo K, Kurppa KJ, Laiho A, et al.
Early dental epithelial transcription factors distinguish ameloblastoma from keratocystic odontogenic tumor.
J Dent Res. 2015; 94(1):101-11 [PubMed] Related Publications
The aim of the study was to characterize the molecular relationship between ameloblastoma and keratocystic odontogenic tumor (KCOT) by means of a genome-wide expression analysis. Total RNA from 27 fresh tumor samples of 15 solid/multicystic intraosseous ameloblastomas and 12 sporadic KCOTs was hybridized on Affymetrix whole genome arrays. Hierarchical clustering separated ameloblastomas and KCOTs into 2 distinct groups. The gene set enrichment analysis based on 303 dental genes showed a similar separation of ameloblastomas and KCOTs. Early dental epithelial markers PITX2, MSX2, DLX2, RUNX1, and ISL1 were differentially overexpressed in ameloblastoma, indicating its dental identity. Also, PTHLH, a hormone involved in tooth eruption and invasive growth, was one of the most differentially upregulated genes in ameloblastoma. The most differentially overexpressed genes in KCOT were squamous epithelial differentiation markers SPRR1A, KRTDAP, and KRT4, as well as DSG1, a component of desmosomal cell-cell junctions. Additonally, the epithelial stem cell marker SOX2 was significantly upregulated in KCOT when compared with ameloblastoma. Taken together, the gene expression profile of ameloblastoma reflects differentiation from dental lamina toward the cap/bell stage of tooth development, as indicated by dental epithelium-specific transcription factors. In contrast, gene expression of KCOT indicates differentiation toward keratinocytes.

Tyszkiewicz T, Jarzab M, Szymczyk C, et al.
Epidermal differentiation complex (locus 1q21) gene expression in head and neck cancer and normal mucosa.
Folia Histochem Cytobiol. 2014; 52(2):79-89 [PubMed] Related Publications
Epidermal differentiation complex (EDC) comprises a number of genes associated with human skin diseases including psoriasis, atopic dermatitis and hyperkeratosis. These genes have also been linked to numerous cancers, among them skin, gastric, colorectal, lung, ovarian and renal carcinomas. The involvement of EDC components encoding S100 proteins, small proline-rich proteins (SPRRs) and other genes in the tumorigenesis of head and neck squamous cell cancer (HNSCC) has been previously suggested. The aim of the study was to systematically analyze the expression of EDC components on the transcript level in HNSCC. Tissue specimens from 93 patients with HNC of oral cavity and 87 samples from adjacent or distant grossly normal oral mucosawere analyzed. 48 samples (24 tumor and 24 corresponding surrounding tissue) were hybridized to Affymetrix GeneChip Human 1.0 ST Arrays. For validation by quantitative real-time PCR (QPCR) the total RNA from all180 samples collected in the study was analyzed with Real-Time PCR system and fluorescent amplicon specific-probes. Additional set of samples from 14 patients with laryngeal carcinoma previously obtained by HG-U133 Plus 2.0 microarray was also included in the analyses. The expression of analyzed EDC genes was heterogeneous. Two transcripts (S100A1 and S100A4) were significantly down-regulated in oral cancer when compared to normal mucosa (0.69 and 0.36-fold change, respectively), showing an opposite pattern of expression to the remaining S100 genes. Significant up-regulation in tumors was found for S100A11, S100A7, LCE3D, S100A3 and S100A2 genes. The increased expression of S100A7 was subsequently validated by QPCR, confirming significant differences. The remaining EDC genes, including all encoding SPRR molecules, did not show any differences between oral cancer and normal mucosa. The observed differences were also assessed in the independent set of laryngeal cancer samples, confirming the role of S100A3 and LCE3D transcripts in HNC. In HNC of oral cavity only one family of EDC genes (S100 proteins) showed significant cancer-related differences. A number of other transcripts which showed altered expression in HNC require further validation.

Zhang H, Gao J, Zhao Z, et al.
Clinical implications of SPRR1A expression in diffuse large B-cell lymphomas: a prospective, observational study.
BMC Cancer. 2014; 14:333 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Certain markers have been identified over the last 10 years that facilitate the prediction of a patient's prognosis; these markers have been proposed to be useful for risk stratification of lymphoma patients and for the development of specific therapeutic strategies. In the present study, we assessed the potential prognostic value of SPRR1A expression in 967 patients with diffuse large B-cell lymphomas.
METHODS: All patients were enrolled between 2001 and 2007 (median follow-up, 53.3 months) in the Second Hospital of Dalian Medical University, First Hospital of China Medical University, and Liaoning Cancer Hospital. Immunohistochemical analysis was used to evaluate the expression of SPRR1A. Survival was analyzed using the Kaplan-Meier method. Multivariate analysis was conducted to adjust the effect of SPRR1A expression for potential, well-known, independent prognostic factors.
RESULTS: Of the 967 patients examined, SPRR1A expression was detected in 305 (31.54%) patients on immunohistochemical analysis. The 5-year survival rate was significantly lower in patients with SPRR1A expression than in those without (26.9% vs. 53.2%, P < 0.001). Multivariate analysis identified SPRR1A expression as an independent predictor of survival in addition to lactate dehydrogenase level, clinical stage, and histologic subtype.
CONCLUSIONS: SPRR1A expression may be useful as a prognostic factor for diffuse large B-cell lymphoma.

Luo A, Yu X, Li G, et al.
Differentiation-associated genes regulated by c-Jun and decreased in the progression of esophageal squamous cell carcinoma.
PLoS One. 2014; 9(5):e96610 [PubMed] Free Access to Full Article Related Publications
Transcription factor c-Jun plays a key role in controlling epithelium cell proliferation, apoptosis and differentiation. However, molecular mechanism and biological functions of c-Jun in squamous differentiation and the progression of esophageal squamous cell carcinoma (ESCC) remain elusive. In this study, we found that c-Jun bound directly to the promoter region, and activated the transcription of differentiation-associated genes including cystatin A, involucrin and SPRR3 in vivo. Ectopic expression of c-Jun enhanced SPRR3 transactivation in KYSE450 cells. Conversely, TAM67, a dominant negative mutant of c-Jun, inhibited SPRR3 transactivation. c-Jun increased expression of SPPR3 mainly via a PKC/JNK pathway in response to TPA in KYSE450 cells. Furthermore, c-Jun was remarkably reduced in esophageal cancer. Interestingly, cystatin A, involucrin and SPRR3 were significantly downregulated as well, and associated with differentiation grade. Expression of c-Jun was correlated with the expression of these genes in normal epithelium and ESCC. Importantly, the expression of these genes was remarkably decreased during the malignant transformation from normal epithelium to low-grade intraepithelial neoplasia (LGIN) or high-grade intraepithelial neoplasia (HGIN). The expression of cystatin A and involucrin was significantly reduced from LGIN to HGIN. These results suggest c-Jun was involved in the regulation of differentiation-associated genes in ESCC. These genes might serve as the potential markers in distinguishing normal epithelium from esophageal squamous intraepithelial neoplasia.

Michifuri Y, Hirohashi Y, Torigoe T, et al.
Small proline-rich protein-1B is overexpressed in human oral squamous cell cancer stem-like cells and is related to their growth through activation of MAP kinase signal.
Biochem Biophys Res Commun. 2013; 439(1):96-102 [PubMed] Related Publications
Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are considered to be essential for tumor maintenance, recurrence and metastasis. Therefore, eradication of CSCs/CICs is essential to cure cancers. However, the molecular mechanisms of CSCs/CICs are still elusive. In this study, we investigated the molecular mechanism of the cell growth of oral CSCs/CICs. Oral CSCs/CICs were isolated as aldehyde dehydrogenase 1 bright (ALDH1(br)) cells by the ALDEFLUOR assay. Small proline-rich protein-1B (SPRR1B) gene was shown to be overexpressed in ALDH1(br) cells by a cDNA microarray and RT-PCR. SPRR1B was shown to have a role in cell growth and maintenance of ALDH1(br) cells by SPRR1B overexpression and knockdown experiments. To elucidate the molecular mechanism by which SPRR1B regulates cell growth, further cDNA microarray analysis was performed using SPRR1B-overexpressed cells and cells with SPRR1B knocked down by siRNA. Expression of the tumor suppressor gene Ras association domain family member 4 (RASSF4) was found to be suppressed in SPRR1B-overexpressed cells. On the other hand, the expression of RASSF4 was enhanced in cells in which SPRR1B expression was knocked down by SPRR1B-specific siRNA. RASSF4 has an RA (Ras association) domain, and we thus hypothesized that RASSF4 modulates the MAP kinase signal downstream of the Ras signal. MAP kinase signal was activated in SPRR1B-overexpressed cells, whereas the signal was suppressed in SPRR1B knocked down cells. Taken together, the results indicate that the expression of SPRR1B is upregulated in oral CSCs/CICs and that SPRR1B has a role in cell growth by suppression of RASSF4.

Kim JC, Yu JH, Cho YK, et al.
Expression of SPRR3 is associated with tumor cell proliferation in less advanced stages of breast cancer.
Breast Cancer Res Treat. 2012; 133(3):909-16 [PubMed] Related Publications
Small proline rich repeat protein 3 (SPRR3), a member of the SPRR family of cornified envelope precursor proteins, is a marker for terminal squamous cell differentiation. Previously, this laboratory showed that SPRR3 is strongly upregulated in colorectal tumors, and is involved in the tumorigenesis. The current study was performed to investigate the expression status and effect of SPRR3 in breast cancers (BCs). SPRR3 expression was examined by immunohistochemistry in 241 tumor samples from BC patients. SPRR3 was overexpressed in more than half of all BC samples. SPRR3 overexpression was significantly associated with less advanced stage (0-1 vs. II-III) and the absence of lymph node metastasis (P = 0.004 and 0.013, respectively). HER2/neu overexpression was closely correlated with SPRR3 overexpression in a multivariate analysis (OR, 3.23, P = 0.017). To assess the influence of SPRR3 on cell proliferation and related signaling pathways, SPRR3-transfected clones from the SPRR3-negative T-47D human BC cell line were generated. Among the total of six SPRR3-overexpressing clones, five showed marked proliferation compared with SPRR3-nonexpressing control cells from day 3 of culture (P < 0.001). The SPRR3-overexpressing BC clones showed increased phosphorylation of AKT and MDM2, p21 overexpression, and p53 downregulation. Furthermore, phosphorylation of MEK and MAPK was markedly increased. This study demonstrates that SPRR3 promotes BC cell proliferation by enhancing p53 degradation via the AKT and MAPK pathways and is, therefore, a potential novel therapeutic target for less advanced stages of BC.

Pasini FS, Maistro S, Snitcovsky I, et al.
Four-gene expression model predictive of lymph node metastases in oral squamous cell carcinoma.
Acta Oncol. 2012; 51(1):77-85 [PubMed] Related Publications
BACKGROUND: Previous knowledge of cervical lymph node compromise may be crucial to choose the best treatment strategy in oral squamous cell carcinoma (OSCC). Here we propose a set four genes, whose mRNA expression in the primary tumor predicts nodal status in OSCC, excluding tongue.
MATERIAL AND METHODS: We identified differentially expressed genes in OSCC with and without compromised lymph nodes using Differential Display RT-PCR. Known genes were chosen to be validated by means of Northern blotting or real time RT-PCR (qRT-PCR). Thereafter we constructed a Nodal Index (NI) using discriminant analysis in a learning set of 35 patients, which was further validated in a second independent group of 20 patients.
RESULTS: Of the 63 differentially expressed known genes identified comparing three lymph node positive (pN +) and three negative (pN0) primary tumors, 23 were analyzed by Northern analysis or RT-PCR in 49 primary tumors. Six genes confirmed as differentially expressed were used to construct a NI, as the best set predictive of lymph nodal status, with the final result including four genes. The NI was able to correctly classify 32 of 35 patients comprising the learning group (88.6%; p = 0.009). Casein kinase 1alpha1 and scavenger receptor class B, member 2 were found to be up regulated in pN + group in contrast to small proline-rich protein 2B and Ras-GTPase activating protein SH3 domain-binding protein 2 which were upregulated in the pN0 group. We validated further our NI in an independent set of 20 primary tumors, 11 of them pN0 and nine pN + with an accuracy of 80.0% (p = 0.012).
CONCLUSIONS: The NI was an independent predictor of compromised lymph nodes, taking into the consideration tumor size and histological grade. The genes identified here that integrate our "Nodal Index" model are predictive of lymph node metastasis in OSCC.

de A Simão T, Souza-Santos PT, de Oliveira DS, et al.
Quantitative evaluation of SPRR3 expression in esophageal squamous cell carcinoma by qPCR and its potential use as a biomarker.
Exp Mol Pathol. 2011; 91(2):584-9 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is highly fatal due to late diagnosis and inefficient treatment. Early disease detection could improve diagnosis and patient survival. Esophageal squamous epithelial cells express SPRR3, a member of the small proline-rich protein family, which is downregulated in ESCC. Therefore, SPRR3 expression may be used as a biomarker to follow the transition from healthy mucosa to ESCC. Both SPRR3 mRNA splice variants, v1 and v2, were evaluated by real time PCR in tumor and histologically normal adjacent tissue biopsies from 84 ESCC patients and 18 healthy controls. SPRR3-v1 was most highly expressed in the esophageal mucosa of healthy subjects, with an increasingly lower expression in the adjacent mucosa of ESCC patients and in tumors, respectively. SPRR3-v2 expression was low in normal mucosa and in tumors but it was higher in the adjacent mucosa of ESCC patients. In addition, we found a significant correlation between a lower SPRR3-v1 and SPRR3-v2 expression and age and alcohol consumption, respectively. SPRR3 protein expression presented a good correlation with SPRR3 mRNA expression. Cut-off points to discriminate between healthy mucosa, tumor and adjacent mucosa were determined with receiver operating characteristic (ROC) curves. This analysis showed that SPRR3-v1 expression discriminates the esophageal mucosa of healthy subjects from the adjacent mucosa and the tumor of ESCC patients with high sensitivity and specificity. Our data shows that the quantitative analysis of SPRR3 mRNA is a robust and reliable method to monitor the malignant transformation of the healthy esophageal mucosa into ESCC.

Cho DH, Jo YK, Roh SA, et al.
Upregulation of SPRR3 promotes colorectal tumorigenesis.
Mol Med. 2010 Jul-Aug; 16(7-8):271-7 [PubMed] Free Access to Full Article Related Publications
Hereditary colorectal cancer develops through a series of well-defined genetic and histological changes. However, elucidation of the canonical pathway based on hereditary colorectal cancer has not provided a clear explanation of the molecular mechanisms of sporadic colorectal cancer. To identify the alterative pathways involved in sporadic colorectal tumorigenesis, we performed gene expression analysis in patients with sporadic colorectal tumors. A comparison analysis of gene expression profiles revealed a pattern of upregulation of small proline rich repeat protein 3 (SPRR3) in tumor samples. SPRR3 has previously been reported to be downregulated in esophageal cancer. However, in the present study, we observed that SPRR3 was strongly upregulated in 31 of 35 samples of sporadic colorectal tumors (88%). We also determined that overexpression of SPRR3 not only accelerates colorectal cancer cell proliferation but also is associated with lymphovascular invasion in colorectal cancer. Moreover, AKT was activated and p53 levels were decreased in cells that overexpressed SPRR3. In contrast to the pattern seen in esophageal cancer, these results suggest that increased expression of SPRR3 is involved in colorectal tumorigenesis.

Kimchi ET, Posner MC, Park JO, et al.
Progression of Barrett's metaplasia to adenocarcinoma is associated with the suppression of the transcriptional programs of epidermal differentiation.
Cancer Res. 2005; 65(8):3146-54 [PubMed] Related Publications
We did expressional profiling on 24 paired samples of normal esophageal epithelium, Barrett's metaplasia, and esophageal adenocarcinomas. Matching tissue samples representing the three different histologic types were obtained from each patient undergoing esophagectomy for adenocarcinoma. Our analysis compared the molecular changes accompanying the transformation of normal squamous epithelium with Barrett's esophagus and adenocarcinoma in individual patients rather than in a random cohort. We tested the hypothesis that expressional profiling may reveal gene sets that can be used as molecular markers of progression from normal esophageal epithelium to Barrett's esophagus and adenocarcinoma. Expressional profiling was done using U133A GeneChip (Affymetrix), which represent approximately two thirds of the human genome. The final selection of 214 genes permitted the discrimination of differential gene expression of normal esophageal squamous epithelium, Barrett's esophagus, and adenocarcinoma using two-dimensional hierarchical clustering of selected genes. These data indicate that transformation of Barrett's esophagus to adenocarcinoma is associated with suppression of the genes involved in epidermal differentiation, including genes in 1q21 loci and corresponding to the epidermal differentiation complex. Correlation analysis of genes concordantly expressed in Barrett's esophagus and adenocarcinoma revealed 21 genes that represent potential genetic markers of disease progression and pharmacologic targets for treatment intervention. PCR analysis of genes selected based on DNA array experiments revealed that estimation of the ratios of GATA6 to SPRR3 allows discrimination among normal esophageal epithelium, Barrett's dysplasia, and adenocarcinoma.

Duffy CL, Phillips SL, Klingelhutz AJ
Microarray analysis identifies differentiation-associated genes regulated by human papillomavirus type 16 E6.
Virology. 2003; 314(1):196-205 [PubMed] Related Publications
In this study, we used oligonucleotide microarray analysis to determine which cellular genes are regulated by the human papillomavirus type 16 (HPV-16) E6 oncoprotein. We found that E6 causes the downregulation of a large number of cellular genes involved in keratinocyte differentiation, including genes such as small proline-rich proteins, transglutaminase, involucrin, elafin, and cytokeratins, which are normally involved in the production of the cornified cell envelope. In contrast, E6 upregulates several genes, such as vimentin, that are usually expressed in mesenchymal lineages. E6 also modulates levels of genes involved in inflammation, including Cox-1 and Nag-1. By using E6 mutants that differentially target p53 for degradation, we determined that E6 regulates cellular genes by both p53-dependent and independent mechanisms. The microarray data also indicate that HPV-16 E6 modulates certain effects of HPV-16 E7 on cellular gene expression. The identification of E6-regulated genes in this analysis provides a basis for further studies on their role in HPV infection and cellular transformation.

Lehr E, Brown DR
Infection with the oncogenic human papillomavirus type 59 alters protein components of the cornified cell envelope.
Virology. 2003; 309(1):53-60 [PubMed] Related Publications
Infection of the genital tract with human papillomaviruses (HPVs) leads to proliferative and dysplastic epithelial lesions. The mechanisms used by the virus to escape the infected keratinocyte are not well understood. Infection of keratinocytes with HPV does not cause lysis, the mechanism used by many viruses to release newly formed virions. For HPV 11, a type associated with a low risk of neoplastic disease, the cornified cell envelope (CCE) of infected keratinocytes is thin and fragile, and transcription of loricrin, the major CCE protein, is reduced. The effects of high-risk HPV infection on components of the CCE have not been previously reported. HPV 59, an oncogenic genital type related to HPV types 18 and 45 was identified in a condylomata acuminata lesion. An extract of this lesion was used to infect human foreskin fragments, which were grown in athymic mice as xenografts. Continued propagation using extracts of xenografts permitted growth of additional HPV 59-infected xenografts. CCEs purified from HPV 59-infected xenografts displayed subtle morphologic abnormalities compared to those derived from uninfected xenografts. HPV 59-infected xenografts revealed dysplastic-appearing cells with mitotic figures. Detection of loricrin, involucrin, and cytokeratin 10 was reduced in HPV 59-infected epithelium, while small proline-rich protein 3 (SPR3) was increased. Reduction in loricrin was most apparent in regions of epithelium containing abundant HPV 59 DNA. Compared to uninfected epithelium, loricrin transcription was decreased in HPV 59-infected epithelium. We conclude that HPV 59 shares with HPV 11 the ability to alter CCE components and to specifically reduce transcription of the loricrin gene. Because loricrin is the major CCE protein, a reduction in this component could alter the physical properties of the CCE, thus facilitating virion release.

Reddy SP, Vuong H, Adiseshaiah P
Interplay between proximal and distal promoter elements is required for squamous differentiation marker induction in the bronchial epithelium: role for ESE-1, Sp1, and AP-1 proteins.
J Biol Chem. 2003; 278(24):21378-87 [PubMed] Related Publications
Overexpression of SPRR1B in bronchial epithelial cells is a marker for early metaplastic changes induced by various toxicants/carcinogens. Previously, we have shown that the transcriptional stimulation of SPRR1B expression by phorbol 12-myristate 13-acetate (PMA) is mainly mediated by a -150/-94 bp enhancer harboring two critical 12-O-tetradecanoylphorbol-13-acetate-responsive elements (TREs) and by Jun.Fra-1 dimers. Here, we show that a region between -54 and -39 bp containing an ETS-binding site (EBS) and a GC box is essential for both basal and PMA-inducible SPRR1B transcription. In vivo footprinting demonstrated binding of transcription factors to these elements. However, unlike enhancer TREs, exposure of cells to PMA did not significantly alter the footprinting pattern at these elements. Mutations that crippled both the EBS and GC box suppressed both basal and PMA-inducible SPRR1B transcription. Consistent with this, overexpression of EBS-binding proteins ESE-1 and ESE-3 significantly stimulated SPRR1B promoter activity. Furthermore, preceding SPRR1B transcription, PMA up-regulated mRNA expression of ETS family members such as ESE-1 and ESE-3. Although ESE-1 synergistically activated c-Jun- and PMA-enhanced SPRR1B transcription, coexpression of Sp1 and ESE-1 showed no synergistic or additive effect on promoter activity, indicating an obligatory role for AP-1 proteins in such regulation. In support of this notion, deletion or mutation of two functional TREs inhibited ESE-1- and Sp1-enhanced promoter activation. Thus, the interaction between ESE-1 and Sp1, and AP-1 proteins that bind to the proximal and distal promoter regions, respectively, play a critical role in the induction of squamous differentiation marker expression in bronchial epithelial cells.

Vuong H, Patterson T, Adiseshaiah P, et al.
JNK1 and AP-1 regulate PMA-inducible squamous differentiation marker expression in Clara-like H441 cells.
Am J Physiol Lung Cell Mol Physiol. 2002; 282(2):L215-25 [PubMed] Related Publications
Exposure of distal bronchiolar region to various toxicants and pollutants suppresses Clara cell differentiation marker expression and greatly enhances the induction of squamous cell differentiation (SCD). Here, we demonstrate for the first time phorbol 13-myristate 12-acetate (PMA)-inducible expression of SCD markers, SPRRs, in Clara-like H441 cells. The transcriptional stimulation of human SPRR1B expression is mainly mediated by a -150- to -84-bp region that harbors two critical activator protein (AP)-1 sites. In unstimulated cells, the -150- to -84-bp region is weakly bound by AP-1 proteins, mainly JunD and Fra1. However, PMA prominently induced the binding of JunB and Fra1. Consistent with this, overexpression of wild-type Jun proteins upregulated the SPRR1B promoter activity. Conversely, a c-jun mutant suppressed both basal and PMA-inducible reporter gene expression. Intriguingly, overexpression of fra2 suppressed PMA-inducible reporter activity, whereas fra1 significantly enhanced basal level activity, indicating an opposing role for these proteins in SPRR1B expression in a manner similar to that observed in proximal tracheobronchial epithelial cells (BEAS-2B clone S6). Interestingly, unlike in S6 cells, a catalytically inactive c-Jun NH(2)-terminal kinase (JNK) 1 mutant significantly reduced the PMA-inducible SPRR1B promoter activity in H441 cells. Thus either temporal expression and/or spatial activation of AP-1 proteins by JNK1 might contribute to the induction of SCD in Clara cells.

Patterson T, Vuong H, Liaw YS, et al.
Mechanism of repression of squamous differentiation marker, SPRR1B, in malignant bronchial epithelial cells: role of critical TRE-sites and its transacting factors.
Oncogene. 2001; 20(5):634-44 [PubMed] Related Publications
The overexpression of SPRR1B in bronchial epithelium is a marker for early metaplastic changes and the loss of its expression is associated with an irreversible malignant transformation. In the present study, we have used a model system consisting of normal and malignant bronchial epithelial (BE) cells to elucidate the differential transcriptional control of SPRR1B. SPRR1B expression is either detectable or PMA (phorbol 13-myristate 12-acetate) -inducible in several malignant BE cells including squamous, adeno, small and large cell carcinomas. Loss of SPRR1B expression is correlated well with the lack of strong in vivo protein-DNA interactions at the -152 bp promoter, which contains two functional TRE sites. Even though the basal level AP-1 protein DNA binding pattern is different between normal and malignant cells, PMA significantly enhances Jun and Fos binding to the consensus TRE site in both cell types. Intriguingly, the composition of AP-1 protein binding to the -152 to -86 bp SPRR1B promoter is quite different. In untreated cells, SPRR1B promoter is predominantly occupied by JunD and Fra2. PMA significantly induced binding of JunB and Fra1 in normal cells, while JunB and Fra2 bound to TREs in the malignant cells. Overexpression of fra1 in malignant cells significantly enhanced SPRR1B promoter activity. In contrast, overexpression of fra2, but not fra1, strongly reduced both basal and PMA-inducible promoter activities in normal cells. Together, these results indicate that either temporal expression and/or differential activation of AP-1 proteins, especially Fra1 and Fra2, might contribute to the dysregulation of terminal differentiation marker, SPRR1B, expression in various BE cells.

Zucchini C, Strippoli P, Rosati G, et al.
Expression analysis and mutational screening of the epithelium-specific ets gene-1 (ESE-1) in patients with squamous anal cancer.
Int J Oncol. 2000; 17(2):265-70 [PubMed] Related Publications
To investigate whether ESE-1 gene abnormalities are involved in alterations of epithelial cell differentiation in squamous anal cancer ESE-1 expression and structure were screened in six patients by reverse transcriptase-polymerase chain reaction (RT-PCR) and automated sequence analysis. The complete cDNA of isoform ESE-1b was always expressed and correctly spliced, with single nucleotide polymorphism being observed in two cases. Presence of ESE-1b point mutations was excluded. Expression of SPRR2A and ENDOA/CK8, two epithelium-specific ESE-1 target genes, were revealed by RT-PCR in all cases. This first report of expression of ESE-1, and of SPRR2A and ENDOA/CK8 (both related to terminal differentiation in different types of epithelia lining) in anal cancer excludes the hypothesis that these genes influenced carcinogenesis in our patients. Despite selecting of patients without clinical evidence of HPV infection, PCR consistently revealed HPV-16 DNA, highlighting the importance of HPV infection in anal cancer.

Lau D, Xue L, Hu R, et al.
Expression and regulation of a molecular marker, SPR1, in multistep bronchial carcinogenesis.
Am J Respir Cell Mol Biol. 2000; 22(1):92-6 [PubMed] Related Publications
A small proline-rich protein, SPR1, is overexpressed in squamous metaplasia of bronchial epithelium. We studied the expression and regulation of SPR1 in a series of human bronchial epithelial cell lines representing a model of multistep bronchial carcinogenesis. These cell lines included a primary culture of tracheobronchial epithelial cells (HTBE), a papilloma virus-transformed tracheobronchial epithelial cell line (HBE1), a cell line selected from HBE1 by a tobacco carcinogen and a phorbol ester (HBE1-C), a simian virus-transformed bronchial epithelial cell line (BEAS-2B), and a lung carcinoma cell line (H460). Different tumorigenic potentials of these cell lines were indicated by graded levels of telomerase activity. Concomitant with squamous transformation, there was an increase in SPR1 expression in HTBE, HBE1, and HBE1-C that was reversible by vitamin A. With progression of tumorigenicity, there was a marked reduction in SPR1 expression in BEAS-2B and a total loss of expression in H460. In these latter cell lines representing advanced malignant transformation, there was a loss of up- and downregulation, respectively, by the phorbol ester and vitamin A. Transfection study with chimeric constructs of the SPR1 promoter and a reporter gene showed that the dysregulation of SPR1 expression in malignant transformation was a result of perturbation of the basal and enhancer elements of the first 162 nucleotides in the 5'-flanking promoter region of the SPR1 gene. These findings suggest an association of transcriptional dysregulation of the SPR1 gene with multistep bronchial carcinogenesis.

Anisowicz A, Sotiropoulou G, Sager R
Re-expression of SPR1 in breast cancer cells by phorbol 12-myristate 13-acetate (PMA) or UV irradiation is mediated by the AP-1 binding site in the SPR1 promoter.
Mol Med. 1999; 5(8):526-41 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Invasive tumor cells are characterized by multiple phenotypic changes as a result of the large number of cDNAs being differentially expressed in tumor cells compared to normal progenitors. Expression genetics focuses on changes at the RNA level with the aim of identifying functionally important genes whose aberrant expression in cancer cells is regulated at the level of transcription. These genes were named class II genes and are distinguished from class I genes, which are characterized by genomic mutations, deletions, or other alterations. Reversal of the tumor cell phenotype accompanying normalization of the expression of such genes may be exploited therapeutically if gene expression can be specifically modulated by drugs or other treatments. Considering that genes are coordinately regulated in complex networks, it is likely that the expression of multiple genes can be simultaneously modulated in tumor cells by drugs acting on the signal transduction pathway that regulates their expression. The SPR1 gene is associated with differentiation and its expression is down-regulated or inactivated in malignant cells. Analysis of the SPR1 promoter showed that down-regulation of SPR1 expression in breast tumor cells occurs at the level of transcription. SPR1 presents an example of class II genes, since its expression was up-regulated in tumor cells by phorbol 12-myristate 13-acetate (PMA) or by ultraviolet (UV) irradiation.
MATERIALS AND METHODS: The SPR1 gene was identified by differential display on the basis of its reduced or absent expression in human breast tumor cell lines compared to normal mammary epithelial cell strains. Differential expression was confirmed by Northern blot analysis employing multiple normal and tumor cell lines. The promoter region -619 to +15 of the SPR1 gene was sequenced and analyzed by CAT assays, deletion analysis, and mutagenesis. Up-regulation of SPR1 expression by PMA and UV irradiation was monitored by Northern analysis and analyzed by CAT assays.
RESULTS: The mechanism of down-regulation of SPR1 expression in breast tumor cells was investigated. It was found that the -619 to +15 upstream promoter region is sufficient for SPR1 expression in normal breast cells, but it is transcriptionally silent in most breast tumor cell lines. By deletion analysis and mutagenesis, two upstream cis-acting promoter elements were identified. Our data indicate that the AP-1 element located between -139 and -133 acts as a major enhancer of SPR1 transcription only in normal mammary epithelial cells but not in corresponding tumor cells, whereas the sequences flanking the AP-1 site do not affect its promoter enhancing activity. In addition, a transcriptional repressor was identified that binds unknown factor(s) and is active in both normal and tumor breast cells. Inhibitor function was mapped to a 35-bp element located from -178 to -139 upstream of the human SPR1 mRNA start site. The expression of SPR1 could be induced in the 21MT-2 metastatic breast tumor cell line by PMA treatment or by short UV irradiation via a transcriptional mechanism. AP-1 is the cis element mediating the transcriptional activation of SPR1 by PMA, which induces the expression of AP-1 factors in 21MT-2 cells. Mutation of the AP-1 site abolishes the induction of SPR1 expression by PMA.
CONCLUSIONS: Our results demonstrate that loss of SPR1 expression in breast tumor cells results from impaired transactivation through the AP-1 site in the SPR1 promoter, as well as from the presence of a negative regulatory element active in both normal and tumor cells. Furthermore, our results provide a basis for therapeutic manipulation of down-regulated genes, such as SPR1, in human cancers.

Tesfaigzi J, Carlson DM
Expression, regulation, and function of the SPR family of proteins. A review.
Cell Biochem Biophys. 1999; 30(2):243-65 [PubMed] Related Publications
The small, proline-rich (SPR) genes consist of three subclasses closely linked on human chromosome 1, a region referred to as the epidermal differentiation complex. SPR genes consist of two exons, with the second exon containing the entire open reading frame. SPRs are expressed in all squamous tissues of the skin, scalp, footpad, vaginal epithelia, and most of the epithelial lining of the digestive tract, including the lip, tongue, esophagus, and forestomach. Although SPR1 is absent in normal mucociliary epithelium of the respiratory tract, epithelia that undergo squamous differentiation in response to vitamin-A deficiency or to injury owing to exposure to environmental toxicants express SPR1. High levels of SPR1 are detected in various diseases and cancers of the skin or respiratory epithelia and in nonkeratinizing papillary adenocarcinomas. SPR expression can be regulated by transcriptional factors, by posttranscriptional factors, or by factors that affect SPR1 mRNA translation or protein turnover. Furthermore, regulation can be affected by the state of cell proliferation. The presence of SPR1 in most of these epithelia, and the absence of SPR3 in normal skin, suggest that these subclasses have distinct functions. Various approaches to the study of the cross-linked envelope (CE) components in identifying SPR1 and SPR2 and in suggesting that SPRs are one of the precursor proteins of the CE. However, expression of SPR1 in nonsquamous tissues and cell lines indicates a function not associated with squamous differentiation. Several studies have demonstrated that SPR1 antibodies react with nuclear proteins and that SPR1 is expressed in cells before entering the G0 phase of the cell cycle. Future studies should clarify the role of SPRs by modifying their contents in CE, and should identify SPR-associated proteins to clarify the cell growth-related role of SPR1.

DeMuth JP, Weaver DA, Crawford EL, et al.
Loss of spr1 expression measurable by quantitative RT-PCR in human bronchogenic carcinoma cell lines.
Am J Respir Cell Mol Biol. 1998; 19(1):25-9 [PubMed] Related Publications
Expression of the small, proline-rich protein (spr1) squamous differentiation marker was measured in five cultured normal and 12 malignant human bronchial epithelial cell (BEC) populations by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Whereas spr1 expression was quantifiable and inducible in all five cultured normal cell populations, in all 12 carcinoma cell lines evaluated it was neither quantifiable nor inducible. Primers spanning the entire spr1 coding sequence amplified full-length PCR product from genomic DNA; therefore, large deletions in the coding region were not responsible for the loss of expression measurable by RT-PCR. This is the first molecular genetic marker reported that distinguishes all normal from all carcinoma cell populations evaluated. Because the spr1 protein is a component of the crosslinked envelope that forms during the squamous differentiation process, we hypothesize that the apparent loss of spr1 gene expression disrupts mechanisms for terminal squamous differentiation in the bronchial epithelium, thereby contributing to malignant transformation.

Jetten AM, Harvat BL
Epidermal differentiation and squamous metaplasia: from stem cell to cell death.
J Dermatol. 1997; 24(11):711-25 [PubMed] Related Publications
Epidermal differentiation is a multi-step process defined by a cascade of interrelated changes in the expression of growth-regulatory and differentiation-specific genes (Fig. 1). Irreversible growth arrest is an early event in epidermal differentiation which occurs when cells transit from the basal to the innermost suprabasal layer of the skin and begin to express squamous-specific genes. In culture, interferon gamma, phorbol esters, confluence and growth in suspension are effective signals to induce irreversible growth arrest and differentiation. The induction of differentiation-specific genes occurs either concomitantly with or following growth arrest and is believed to be linked to the molecular events that control irreversible growth arrest. Such a link has been demonstrated in other cell systems undergoing terminal differentiation, such as myogenesis and adipogenesis. Genes encoding proteins involved in the formation of the cross-linked envelope are one set of squamous-specific genes which are induced in the suprabasal layers and include transglutaminase I and III, involucrin, loricrin and cornifins/small proline-rich proteins. Squamous-specific genes exhibit not only different patterns of tissue-specific expression but are also induced at different stages during differentiation, suggesting that transcription of individual genes is regulated by distinct mechanisms. The latter is supported by the identification of different sets of regulatory elements controlling the transcription of these genes. The importance of understanding both the mechanisms that regulate growth arrest and the differentiation program is emphasized by the association found between specific skin diseases and genetic alterations in growth-regulatory genes as well as differentiation markers. In addition, studies into those mechanisms will provide insight into the control of squamous metaplasia and the development of squamous cell carcinomas.

Copper MP, Klaassen I, Brakenhoff RH, et al.
All-trans retinoic acid induced gene expression and growth inhibition in head and neck cancer cell lines.
Oral Oncol. 1997; 33(4):270-4 [PubMed] Related Publications
Retinoids are natural and synthetic analogues of vitamin A and have proven activity in various types of cancer. As for head and neck squamous cell cancer (HNSCC), retinoids are especially active in leukoplakia and in preventing second primary cancers. The aim of this study was to assess the growth inhibiting activity of all-trans retinoic acid (all-trans RA) in a panel of six head and neck squamous cell cancer cell lines and to correlate this response to the mRNA expression of factors related to differentiation and receptor mediated signal transduction. Three lines showed minimal, two moderate and one strong growth inhibition after 72 h exposure to all-trans RA. Three lines with a dissimilar response were selected for further studies, the measurement of mRNA expression by northern blotting. It was found that neither the expression nor the induction of retinoic acid receptor (RAR)-alpha and -gamma and retinoic X receptor-alpha mRNA war related to sensitivity. The mRNA expression of RAR-beta was too low to be measured in the three cell lines. The most sensitive cell line was, however, the only one that expressed mRNA of squamous differentiation markers. These data suggest a relationship between the retinoid sensitivity profile and the degree of cellular differentiation.

Lohman FP, Gibbs S, Fischer DF, et al.
Involvement of c-JUN in the regulation of terminal differentiation genes in normal and malignant keratinocytes.
Oncogene. 1997; 14(13):1623-7 [PubMed] Related Publications
In stratifying cultures of human keratinocytes, expression of the proto-oncoprotein c-JUN and the small proline rich 2 (SPRR2) protein, a precursor of the cornified cell envelope, are inversely related. Whereas c-JUN is typically found in basal proliferating cells, SPRR2 is restricted to suprabasal differentiating layers. Malignant keratinocytes (derived from squamous cell carcinoma, SCC) have reduced sprr2 expression, consistent with their low potential to differentiate, and express c-jun at higher levels than normal keratinocytes. A direct relation between c-jun and sprr2 expression was shown in several ways: transient ectopic expression of c-jun inhibits sprr2a promoter activity in normal differentiating cells, whereas in malignant keratinocytes a dominant negative c-jun mutant restored at least partially both the low promoter activity and the expression of endogenous sprr2. These effects are mediated via a 134 bp promoter fragment which does not include the sprr2a AP-1 binding site. Interestingly, in an SCC cell line, constitutively expressing the dominant c-jun mutant, expression of the terminal differentiation marker involucrin is also strongly increased, suggesting that c-JUN is a general modulator of keratinocyte terminal differentiation rather than only affecting the expression of sprr2.

Lohman FP, Medema JK, Gibbs S, et al.
Expression of the SPRR cornification genes is differentially affected by carcinogenic transformation.
Exp Cell Res. 1997; 231(1):141-8 [PubMed] Related Publications
The small proline rich protein (SPRR) genes constitute a family of conserved genes which are part of the human epidermal differentiation complex (EDC) on chromosome 1q21 and code for precursor proteins of the cornified cell envelope. The expression of these genes is strictly linked to keratinocyte terminal differentiation both in vivo and in vitro. Here we show that cultured cell lines derived from squamous cell carcinoma (SCC) show significantly lower levels of SPRR expression than normal human keratinocytes. However, the residual SPRR expression in SCC lines appears to be both gene and cell line specific. Expression of SPRR2 appears to correlate well with the residual ability of these cells to differentiate. However, the kinetics of SPRR2 expression, following treatment with calcium, an inducer of keratinocyte differentiation, are typical for each cell line and differ substantially from the ones found in normal cells. In most cell lines a rapid transient expression of SPRR2 contrasts with a slow induction leading to a high sustained level of expression in normal cells. This pattern of expression is typical for SPRR2 and not observed for the other SPRR genes or involucrin. Our analysis indicates that the expression of various keratinocyte terminal differentiation markers, even when involved in the same biological process (cornification), can be differentially affected by carcinogenic transformation.

Abraham JM, Wang S, Suzuki H, et al.
Esophagin cDNA cloning and characterization: a tissue-specific member of the small proline-rich protein family that is not expressed in esophageal tumors.
Cell Growth Differ. 1996; 7(7):855-60 [PubMed] Related Publications
Cancer may be understood as the net effect of differences in gene expression between normal and transformed cells. In a novel direct approach applying this principle, complete genes expressed at altered mRNA levels in malignant versus normal esophageal epithelium were identified and isolated from cDNA libraries. One clone was expressed in normal esophageal mucosae but absent in esophageal carcinomas. By in situ hybridization, Northern blotting, and immunohistochemistry, expression of this gene was restricted to normal esophageal mucosa; it is designated esophagin. Esophagin expression was greatest in the superficial, most mature layers of esophageal squamous mucosa and was restricted to this organ, being undetectable in other squamous epithelia. A genomic clone localized esophagin to chromosomal region 1q21-q22. The expressed protein contains multiple direct repeats of an 8-amino acid motif rich in proline, with significant homology to the cornifin, pig 20K, monkey MT5, and human small proline-rich genes spri and spril. Esophagin constitutes the newest and largest member of this small proline-rich gene family and is associated with differentiation and the benign phenotype of the human esophageal epithelial cell.

Kartasova T, Darwiche N, Kohno Y, et al.
Sequence and expression patterns of mouse SPR1: Correlation of expression with epithelial function.
J Invest Dermatol. 1996; 106(2):294-304 [PubMed] Related Publications
A final event in the terminal differentiation of stratified squamous epithelia is the formation of a cornified cell envelope, which is a complex of several proteins cross-linked together by transglutaminases. One set of proteins is the family of small proline rich (SPR) proteins. In human foreskin epidermal cell envelopes, SPRs serve as cross-bridging proteins among the more abundant loricrin. In order to study further their evolution and expression, we have isolated and sequenced cDNAs encoding two mouse SPR1 proteins, SPR1a and SPR1b Comparative sequence analysis showed the preservation of the overall structure of mammalian SPR1 proteins with highly conserved termini and a central peptide domain repeated 13 (SPE1a) or seven (SPR1b) times. Tissues obtained from mouse fetal, newborn, and adult skin were tested by Northern blot analyses, in situ hybridization and immunohistochemistry using an antibody raised to a synthetic peptide corresponding to the C terminus of the SPR1a protein. Skin expression was first detected in fetal periderm in anagen hair follicles of newborn and older mice, and in the thickened epidermis of the lip and footpad, but no signal was detected in interfollicular trunk epidermis. High levels of SPR1a expression were found in epithelia from the forestomach and penis, and in benign squamous papillomas. Other epithelia expressing SPR1a include the tongue, esophagus, and vagina. Whenever detected, SPR1a positive staining was present in the spinous and granular layers. In the forestomach and papillomas, the periphery of cells in the cornified layer was also stained. Our results suggest that SPR1a participates widely in the construction of cell envelopes in cornifying epithelia characterized by either increased thickness or a requirement for extreme flexibility. Based on its likely function as a cross-bridging protein in cell envelopes, we conclude that the mechanical attributes of cell envelopes may be determined in part by the SPR1 content, in accordance with the specific function of the epithelium.

Yaar M, Eller MS, Bhawan J, et al.
In vivo and in vitro SPRR1 gene expression in normal and malignant keratinocytes.
Exp Cell Res. 1995; 217(2):217-26 [PubMed] Related Publications
The small proline-rich protein 1 (SPRR1) gene encodes a precursor of the keratinocyte cornified envelope. To understand SPRR1 regulation we investigated its expression and modulation in keratinocytes in vivo and in vitro. SPRR1 was strongly expressed in suprabasal layers of the epidermis in newborn skin but only weakly expressed in adult skin. Both in vivo and in vitro, SPRR1 was not expressed in undifferentiated cells of basal or squamous carcinomas. However, within the same tumors and in premalignant lesions of squamous cell origin, cells with histologic evidence of differentiation showed a relative increase in SPRR1 transcript level. Within 24 h physiologic doses of uv irradiation induced SPRR1 mRNA in vivo. To investigate the possibility that SPRR1 expression is regulated by uv-induced cytokines, keratinocytes were stimulated with interleukin-1 (IL-1) and interleukin-3 (IL-3). Both significantly induced SPRR1 mRNA, while TGF-beta, known to lower IL-1 receptor in keratinocytes, down-regulated it. Moreover, proximity to inflammatory cells in vivo was associated with SPRR1 induction in anaplastic tumor cells. Our data suggest that SPRR1 is induced early in differentiation of normal keratinocytes but is not expressed in anaplastic cells of keratinocyte origin. Further, its regulation in skin appears to be modulated at least in part through cytokine release.

Robinson PA, Marley JJ, High AS, Hume WJ
Differential expression of protease inhibitor and small proline-rich protein genes between normal human oral tissue and odontogenic keratocysts.
Arch Oral Biol. 1994; 39(3):251-9 [PubMed] Related Publications
The technique of differential hybridization was used to compare gene transcription between normal oral mucosa and odontogenic keratocyst lining. Protease inhibitors, elafin and stefin-B as well as beta-actin and two epithelial-specific small proline-rich (spr) proteins, which we have named SPRC and SPRK and which are distinct from salivary proline-rich proteins, were differentially expressed. Increased abundance of alpha I(I) collagen and elafin transcripts was demonstrated in the keratocyst, with decreased abundance of stefin B, SPRC and cytokeratins 4 and 13 transcripts compared to normal palatal mucosa. The deduced protein sequences of SPRC and SPRK were described and compared, and the relative abundance of their respective cDNAs in palatal and keratocyst libraries determined. Identification of factors controlling transcription of these genes could advance our understanding of the development of odontogenic keratocysts.

Saunders NA, Jetten AM
Control of growth regulatory and differentiation-specific genes in human epidermal keratinocytes by interferon gamma. Antagonism by retinoic acid and transforming growth factor beta 1.
J Biol Chem. 1994; 269(3):2016-22 [PubMed] Related Publications
Interferon gamma (IFN-gamma) is a potent inducer of squamous differentiation in normal human epidermal keratinocytes. This induction is characterized by a > or = 95% decrease in the mRNA level of two growth regulatory genes, cdc2 and E2F-1, and a 7-15-fold increase in the expression of two squamous cell-specific genes, transglutaminase type I and cornifin. In contrast to the decrease in cdc2 and E2F-1 expression, the increase in transglutaminase type I and cornifin mRNAs by IFN-gamma occurs after a lagtime of more than 12 h. These results are consistent with the hypothesis that in normal human epidermal keratinocyte cells irreversible growth arrest precedes the expression of the squamous-differentiated phenotype. The action of IFN-gamma on the expression of squamous cell-specific genes is antagonized by retinoic acid and transforming growth factor beta 1. Both factors are potent suppressors of the induction of transglutaminase type I and cornifin; however, they do not prevent the commitment to irreversible growth arrest. Several squamous cell carcinoma cell lines do not show a detectable decrease in cdc2 or increase in transglutaminase type I mRNA levels after IFN-gamma treatment and appear to be altered in their control of squamous differentiation.

Fujimoto W, Marvin KW, George MD, et al.
Expression of cornifin in squamous differentiating epithelial tissues, including psoriatic and retinoic acid-treated skin.
J Invest Dermatol. 1993; 101(3):268-74 [PubMed] Related Publications
The expression of cornifin, a putative cross-linked envelope precursor, was investigated in several squamous differentiating tissues by in situ hybridization and immunohistochemical analysis. Cornifin mRNA and protein, which are absent in the normal mucociliary tracheal epithelium, are induced in the suprabasal layers of the squamous metaplastic tracheal epithelium of vitamin A-deficient hamsters. Similar to the induction of squamous metaplasia in vivo, culture of rabbit tracheal cells in the absence of retinoids results in squamous differentiation and expression of cornifin. This induction of cornifin expression is suppressed by retinoic acid and several of its analogs. Cornifin mRNA and protein are also detected in the suprabasal layers of the squamous epithelium of rabbit esophagus and tongue. The distribution of cornifin in human epidermis was compared with that of two other crosslinked envelope precursor proteins, involucrin and loricrin. The localization of cornifin and involucrin is very similar. Both are induced in the spinous layer and appear at an earlier stage during epidermal differentiation than loricrin. The expression of cornifin is greatly increased in psoriatic skin. Cornifin mRNA is barely detectable in normal epidermis, whereas it is present at relatively high levels in the suprabasal layers of psoriatic epidermis. Topical treatment with RA results in thickening of the skin and increases the level of cornifin mRNA and protein in the upper spinous layers of mouse skin. Cornifin expression correlates generally with squamous differentiation in a variety of tissues and is abnormally regulated in psoriatic skin and in skin treated topically with retinoic acid.

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