Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0282612 (PIN)
 2,291 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dual inactivation of PTEN and INK4a/ARF tumor suppressor genes is a common feature observed in a broad spectrum of human cancer types. To validate functional collaboration between these genes in tumor suppression, we examined the biological consequences of Pten and/or Ink4a/Arf deficiency in cells and mice. Relative to single mutant controls, Ink4a/Arf-/-Pten+/- mouse embryonic fibroblast cultures exhibited faster rates of growth in reduced serum, grew to higher saturation densities, produced more colonies upon low density seeding, and showed increased susceptibility to transformation by oncogenic H-Ras. Ink4a/Arf deficiency reduced tumor-free survival and shortened the latency of neoplasias associated with Pten heterozygosity, specifically pheochromocytoma, prostatic intraepithelial neoplasia, and endometrial hyperplasia. Compound mutant mice also exhibited an expanded spectrum of tumor types including melanoma and squamous cell carcinoma. Functional synergy between Ink4a/Arf and Pten manifested most prominently in the development of pheochromocytoma, prompting an analysis of genes and loci implicated in this rare human neoplasm. The classical pheochromocytoma genes Ret, Vhl, and Nf-1 remained intact, a finding consistent with the intersection of these genes with pathways engaged by Pten and Ink4a/Arf. Notably, conventional and array-comparative genomic hybridization revealed frequent loss of distal mouse chromosome 4 in a region syntenic to human chromosome 1p that is implicated in human pheochromocytoma. This study provides genetic evidence of collaboration between Pten and Ink4a/Arf in constraining the growth and oncogenic transformation of cultured cells and in suppressing a wide spectrum of tumors in vivo.
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PMID:Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice. 1181 30

The tumor suppressor gene CDKN2/MTSI(p16(INK4)) may be inactivated by point mutations, deletions, or methylation in many tumor types. In prostate cancer, a very low frequency of point mutations has been reported, but deletions of 9p21 and inactivation by methylation are observed more frequently. The purpose of this study was to assess the expression pattern of the CDKN2 protein product p 16 in a series of 104 prostatic adenocarcinomas treated by radical prostatectomy, using immunohistochemical detection on archival, paraffin-embedded material. Nuclear staining was completely absent in 13 (13%) of 104 cases, whereas cytoplasmic staining was found in 99 (95%) of 104 carcinomas. Significant differences were found when comparing the staining intensity of carcinomas and coexisting prostatic intraepithelial neoplasia (PIN) with benign/hyperplastic glands. In 86 (95%) of 91 cases the overall staining intensity of carcinomas was stronger than the reactivity in benign/hyperplastic glands, which were most often weakly stained. In 71 (95%) of 75 cases the staining intensity of PIN was stronger than in benign/hyperplastic glands, a contrast also observed within single glands. However, p16 immunostaining in carcinomas was not prognostically important and it was not associated with standard clinicopathologic parameters. Our results support that CDKN2/plb is inactivated in only a small proportion of localized prostate cancers. The increased p16 staining of carcinomas/PIN in comparison with benign/hyperplastic glands suggests that p 16 protein may be involved in early stages of prostate tumorigenesis by mechanisms other than CDKN2/p16 gene inactivation, and the possibility of using p(16) immunostaining as a marker for PIN is discussed.
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PMID:Expression of p 16 protein in prostatic adenocarcinomas, intraepithelial neoplasia, and benign/hyperplastic glands. 2122 61

The tumor suppressor p16Ink4a, encoded by the INK4a gene, is an inhibitor of cyclin D-dependent kinases 4 and 6, CDK4 and CDK6. This inhibition prevents the phosphorylation of the retinoblastoma protein (pRb), resulting in cellular senescence through inhibition of E2F-mediated transcription of S phase genes required for cell proliferation. The p16Ink4a plays an important role in tumor suppression, whereby its deletion, mutation, or epigenetic silencing is a frequently observed genetic alteration in prostate cancer. To assess its roles and related molecular mechanisms in prostate cancer initiation and progression, we generated a mouse model with conditional deletion of p16Ink4a in prostatic luminal epithelium. The mice underwent oncogenic transformation and developed prostatic intraepithelial neoplasia (PIN) from eight months of age, but failed to develop prostatic tumors. Given the prevalence of aberrant androgen signaling pathways in prostate cancer initiation and progression, we then generated R26hARL/wt:p16L/L: PB-Cre4 compound mice, in which conditional expression of the human AR transgene and deletion of p16Ink4a co-occur in prostatic luminal epithelial cells. While R26hARL/wt:PB-Cre4 mice showed no visible pathological changes, R26hARL/wt:p16L/L: PB-Cre4 compound mice displayed an early onset of high-grade PIN (HGPIN), prostatic carcinoma, and metastatic lesions. Strikingly, we observed tumors resembling human sarcomatoid carcinoma with intermixed focal regions of signet ring cell carcinoma (SRCC) in the prostates of the compound mice. Further characterization of these tumors showed they were of luminal epithelial cell origin, and featured characteristics of epithelial to mesenchymal transition (EMT) with enhanced proliferative and invasive capabilities. Our results not only implicate a biological role for AR expression and p16Ink4a deletion in the pathogenesis of prostatic SRCC, but also provide a new and unique genetically engineered mouse (GEM) model for investigating the molecular mechanisms for SRCC development.
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PMID:Deletion of the p16INK4a tumor suppressor and expression of the androgen receptor induce sarcomatoid carcinomas with signet ring cells in the mouse prostate. 3067 79