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Murine mesenchymal cells that express elevated levels of the CDK inhibitor p16(Ink4a) in vivo are not necessarily senescent.

ABSTRACT: Age-related health decline has been attributed to the accumulation of senescent cells recognized in vivo by p16(Ink4a) expression. The pharmacological elimination of p16(Ink4a)-positive cells from the tissues of mice was shown to extend a healthy lifespan. Here, we describe a population of mesenchymal cells isolated from mice that are highly p16(INK4a)-positive are proficient in proliferation but lack other properties of cellular senescence. These data, along with earlier reports on p16(Ink4a)-positive macrophages, indicate that p16(Ink4a)-positive and senescent cell populations only partially intersect, therefore, extending the list of potential cellular targets for anti- aging therapies.

SUBMITTER: Frescas D

PROVIDER: S-EPMC5584871 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Murine mesenchymal cells that express elevated levels of the CDK inhibitor p16(Ink4a) in vivo are not necessarily senescent.

Frescas David D Hall Brandon M BM Strom Evguenia E Virtuoso Lauren P LP Gupta Mahima M Gleiberman Anatoli S AS Rydkina Elena E Balan Vitaly V Vujcic Slavoljub S Chernova Olga B OB Gudkov Andrei V AV

Cell cycle (Georgetown, Tex.) 20170626 16

Age-related health decline has been attributed to the accumulation of senescent cells recognized in vivo by p16(Ink4a) expression. The pharmacological elimination of p16(Ink4a)-positive cells from the tissues of mice was shown to extend a healthy lifespan. Here, we describe a population of mesenchymal cells isolated from mice that are highly p16(INK4a)-positive are proficient in proliferation but lack other properties of cellular senescence. These data, along with earlier reports on p16(Ink4a)-p ...[more]

PMID: 28650766

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Somatic p16(INK4a) loss accelerates melanomagenesis.

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p16(INK4a) translation suppressed by miR-24.

Project description:Expression of the tumor suppressor p16(INK4a) increases during aging and replicative senescence.Here, we report that the microRNA miR-24 suppresses p16 expression in human diploid fibroblasts and cervical carcinoma cells. Increased p16 expression with replicative senescence was associated with decreased levels of miR-24, a microRNA that was predicted to associate with the p16 mRNA coding and 3'-untranslated regions. Ectopic miR-24 overexpression reduced p16 protein but not p16 mRNA levels. Conversely, introduction of antisense (AS)-miR-24 blocked miR-24 expression and markedly enhanced p16 protein levels, p16 translation, and the production of EGFP-p16 reporter bearing the miR-24 target recognition sites.Together, our results suggest that miR-24 represses the initiation and elongation phases of p16 translation.

| S-EPMC2274865 | biostudies-literature

FOXA1 mediates p16(INK4a) activation during cellular senescence.

Project description:Mechanisms governing the transcription of p16(INK4a), one of the master regulators of cellular senescence, have been extensively studied. However, little is known about chromatin dynamics taking place at its promoter and distal enhancer. Here, we report that Forkhead box A1 protein (FOXA1) is significantly upregulated in both replicative and oncogene-induced senescence, and in turn activates transcription of p16(INK4a) through multiple mechanisms. In addition to acting as a classic sequence-specific transcriptional activator, FOXA1 binding leads to a decrease in nucleosome density at the p16(INK4a) promoter in senescent fibroblasts. Moreover, FOXA1, itself a direct target of Polycomb-mediated repression, antagonizes Polycomb function at the p16(INK4a) locus. Finally, a systematic survey of putative FOXA1 binding sites in the p16(INK4a) genomic region revealed an ∼150 kb distal element that could loop back to the promoter and potentiate p16(INK4a) expression. Overall, our findings establish several mechanisms by which FOXA1 controls p16(INK4a) expression during cellular senescence.

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Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells.

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| S-EPMC4993332 | biostudies-literature

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