Disease relevance of TMEPAI

• PMEPA1, a transforming growth factor-beta-induced marker of terminal colonocyte differentiation whose expression is maintained in primary and metastatic colon cancer [1].
• Moreover, as PMEPA1 expression is maintained, presumptively in a TGF-beta-independent manner after malignant transformation and metastasis, it demonstrates that even late colon cancers retain a strong capacity to execute many steps of the normal colonic differentiation program [1].
• Using differential display-polymerase chain reaction, we identified a novel gene sequence, designated solid tumor-associated gene 1 (STAG1), that is upregulated in renal cell carcinoma (RCC) [2].
• EGF- and cell-cycle-regulated STAG1/PMEPA1/ERG1.2 belongs to a conserved gene family and is overexpressed and amplified in breast and ovarian cancer [3].
• In contrast, STAG1/PMEPA1 expression was barely detectable in leukemia and lymphoma samples [2].
• These findings underscore that the decreased PMEPA1 expression frequently noted in prostate cancers may lead to increased AR functions and strengthen the biological role of PMEPA1 in prostate cancers [4].

High impact information on TMEPAI

• Here, we demonstrate that PMEPA1 protein through its PY motifs interacts with WW domains of the human NEDD4 protein [5].
• PMEPA1 was identified as a gene highly up-regulated by TGF-beta treatment of VACO 330 [1].
• Exogenous expression of PMEPA1, in widely used CaP cell lines DU145, PC3, LNCaP, and LNCaP sublines (C4, C4-2, and C4-2B), conferred cell growth inhibition, and at least one of the PY motifs of PMEPA1 may be involved in its cell growth inhibitory functions [5].
• Intriguingly, in situ hybridization and Northern blot analysis showed that the expression of PMEPA1 was well maintained both in colon cancer primary tumors and in colon cancer liver metastases [1].
• PMEPA1 expression is prostate abundant and restricted to prostatic epithelial cells [5].

Chemical compound and disease context of TMEPAI

• The PMEPA1 gene, a potent inhibitor of prostate cancer cell growth is an androgen-regulated gene [6].

Biological context of TMEPAI

• A novel androgen-regulated gene, PMEPA1, located on chromosome 20q13 exhibits high level expression in prostate [7].
• Analysis of expressed sequence tag databases showed that STAG1/PMEPA1 also was expressed in pancreatic, endometrial, and prostatic adenocarcinomas [2].
• The open reading frame of the androgen-induced RNA (PMEPA1) was characterized as a 759-bp nucleotide sequence coding for a 252-amino-acid protein [7].
• Comparison to genomic clones showed that STAG1/PMEPA1 was located on chromosome 20q13 between microsatellite markers D20S183 and D20S173 and spanned four exons and three introns [2].
• We investigated whether prostate - specific G protein couple receptor genes and STAG1/PMEPA1 gene expression in peripheral- blood could be useful as a diagnostic or prognostic marker of prostate cancer [8].

Anatomical context of TMEPAI

• Northern blot analysis confirmed TGF-beta induction of PMEPA1 in VACO 330, as well as a panel of three other TGF-beta-sensitive colon cell lines [1].
• Consistent with TGF-beta playing a role in terminal differentiation of colonocytes, in situ hybridization of normal colonic epithelium localized PMEPA1 expression to nonproliferating, terminally differentiated epithelium located at the top of colonic crypts [1].

Associations of TMEPAI with chemical compounds

• Taken together, PMEPA1 negatively regulates growth of androgen responsive or refractory CaP cells, and these functions may be mediated through the interaction of PMEPA1 with the NEDD4 protein involved in the ubiquitin-proteasome pathway [5].
• The STAG1/PMEPA1 cDNA encodes a 287-amino-acid protein containing a putative transmembrane domain and motifs that suggest that it may bind src homology 3- and tryptophan tryptophan domain-containing proteins [2].

Physical interactions of TMEPAI

• We addressed the question of whether or not androgen receptor can directly bind to specific PMEPA1 promoter upstream sequences [6].

Other interactions of TMEPAI

• PMEPA1 is thus a novel TGF-beta-induced marker of a differentiated crypt cell population [1].

Analytical, diagnostic and therapeutic context of TMEPAI

• Evaluation of PMEPA1 expression in androgen-dependent/independent tumors of the CWR22 xenograft model revealed that PMEPA1 was overexpressed in three of four androgen-independent tumor tissues [7].
• Androgen receptor binding to predicted promoter upstream sequences of the PMEPA1 gene was confirmed by chromatin immunoprecipitation assay [6].
• RT-PCR amplified PSGR in 8 of 11 untreated and in 9 of 11 treated patients with CaP and in 16 of 20 with BPH; whereas it amplified PMEPA1 in 1 of 11 untreated and in 7 of 11 treated patients with CaP and in 4 of 20 with BPH [8].

References