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A quantitative model for age-dependent expression of the p16INK4a tumor suppressor.

ABSTRACT: Recent work has shown that expression of the p16(INK4a) tumor suppressor increases with chronological age. Expression is accelerated by gerontogenic behaviors such as tobacco use and physical inactivity, and is also influenced by allelic genotype of a polymorphic single nucleotide polymorphism (SNP) rs10757278 that is physically linked with the p16(INK4a) ORF. To understand the relationship between p16(INK4a) expression, chronologic age, subject characteristics and host genetics, we sought to develop a mathematical model that links p16(INK4a) expression with aging. Using an annotated dataset of 170 healthy adults for whom p16(INK4a) expression and subject genotypes were known, we developed two alternative stochastic models that relate p16(INK4a) expression to age, smoking, exercise and rs10757278 genotype. Levels of p16(INK4a) increased exponentially and then saturated at later chronologic ages. The model, which best fit the data, suggests saturation occurs because of p16(INK4a)-dependent attrition of subjects at older chronologic ages, presumably due to death or chronic illness. An important feature of our model is that factors that contribute to death in a non p16(INK4a)-dependent manner do not affect our analysis. Interestingly, tobacco-related increases in p16(INK4a) expression are predicted to arise from a decrease in the rate of p16(INK4a)-dependent death. This analysis is most consistent with the model that p16(INK4a) expression monotonically increases with age, and higher expression is associated with increased subject attrition.

SUBMITTER: Tsygankov D

PROVIDER: S-EPMC2757807 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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A quantitative model for age-dependent expression of the p16INK4a tumor suppressor.

Tsygankov Denis D Liu Yan Y Sanoff Hanna K HK Sharpless Norman E NE Elston Timothy C TC

Proceedings of the National Academy of Sciences of the United States of America 20090914 39

Recent work has shown that expression of the p16(INK4a) tumor suppressor increases with chronological age. Expression is accelerated by gerontogenic behaviors such as tobacco use and physical inactivity, and is also influenced by allelic genotype of a polymorphic single nucleotide polymorphism (SNP) rs10757278 that is physically linked with the p16(INK4a) ORF. To understand the relationship between p16(INK4a) expression, chronologic age, subject characteristics and host genetics, we sought to de ...[more]

PMID: 19805338

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Project description: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.

Dataset Information

A quantitative model for age-dependent expression of the p16INK4a tumor suppressor.

Publications

A quantitative model for age-dependent expression of the p16INK4a tumor suppressor.

Similar Datasets

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