Cellular senescence and tumor suppressor gene p16

Abstract

Cellular senescence is an irreversible arrest of cell growth. Biochemical and morphological changes occur during cellular senescence, including the formation of a unique cellular morphology such as flattened cytoplasm. Function of mitochondria, endoplasmic reticulum and lysosomes are affected resulting in the inhibition of lysosomal and proteosomal pathways. Cellular senescence can be triggered by a number of factors including, aging, DNA damage, oncogene activation and oxidative stress. While the molecular mechanism of senescence involves p16 and p53 tumor suppressor genes and telomere shortening, this review is focused on the mechanism of p16 control. The p16 mediated senescence acts through the retinoblastoma (Rb) pathway inhibiting the action of the cyclin dependant kinases leading to G1 cell cycle arrest. Rb is maintained in a hypophosphorylated state resulting in the inhibition of transcription factor E2F1. Regulation of p16 expression is complex and involves epigenetic control and multiple transcription factors. PRC1 (Pombe repressor complex 1) and PRC2 (Pombe repressor complex 2) proteins and histone deacetylases play an important role in the promoter hypermethylation for suppressing p16 expression. While transcription factors YY1 and Id1 suppress p16 expression, transcription factors CTCF, Sp1, and Ets family members activate p16 transcription. Senescence occurs with the inactivation of suppressor elements leading to the enhanced expression of p16.

Mechanisms of Lung Fibrosis Resolution

“…Senescent cells are refractory to mitogenic stimulation by activating regulators of cell cycle progression, including p53, p21, and p16. 77,78 Extrinsic senescence develops after cellular damage or stress and is hypothesized to be an important mechanism to constrain the malignant progression of tumor cells. 79 Replicative senescence is an intrinsic mechanism whereby there is a limitation in the number of times that cells can divide and is believed to contribute to aging-related pathologies by the acquisition of the senescence-associated secretory phenotype, which enables cells to secrete a variety of growth factors, cytokines, and proteases, which contribute to age-related tissue dysfunction.…”

Human papillomavirus DNA load and p16INK4aexpression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy

“…47 Notably, p16 INK4a expression was evident in two of the four HPV DNA negative patients. As p16 INK4A has been reported to be further regulated by epigenetic control and multiple transcription factors or gain of function in chromosome 11q, 48 it is likely that HPV-negative and HPV-positive anal cancers with low viral load share comparable genetic alterations or epigenetic methylation profiles that might result in reduced sensitivity to RT/CRT and worse prognosis. 32,49,50 We would like to acknowledge the limitations of our study.…”

Association of ANRIL Gene Polymorphisms with Acute Myeloid Leukemia in an Iranian Population

“…These important proteins, are alternate reading frames of the CDKN2A and CDKN2B genes that encodes cyclindependent kinase inhibitors which all act in response to el- evated oncogenic signals such as aberrant growth stimulation and interacts with CDK members of the cell cycle regulation pathways which leads to cell cycle arrest and apoptosis (10)(11)(12). The expression of the INK4b-ARF-INK4a gene cluster is controlled by the Polycomb group (PcG) proteins that serve to maintain the silent chromatin state of the INK4 locus (13).…”