Expression of p16INK4a prevents cancer and promotes aging in lymphocytes

Abstract

Previous authors have suggested that tumor suppressor expression promotes aging while preventing cancer, but direct experimental support for this canceraging hypothesis has been elusive. Here, by using somatic, tissue-specific inactivation of the p16 INK4a IntroductionAntagonistic pleiotropy, one of the oldest hypotheses of aging, suggests that certain cellular activities may be of physiologic benefit in youth but may untowardly decrease organismal fitness in later life. 1 The cancer-aging hypothesis represents a special case of this model, suggesting that tumor suppressor mechanisms such as cellular senescence can function in an antagonistically pleiotropic manner, ie, preventing malignant transformation in young mammals but promoting aging over a lifespan. Although there are examples of senescence-promoting tumor suppressor proteins such as p16 INK4a and p53 contributing to the aging of distinct tissue compartments (reviewed in Campisi 2 and Collado et al 3 ), it has not been possible to directly demonstrate a strict trade-off between increased aging and reduced cancer as the result of a cellautonomous activation of a specific tumor suppressor mechanism within an isolated tissue.The p16 INK4a tumor suppressor, along with 2 other tumor suppressor proteins, p15INK4b and p14 ARF (hereafter referred to solely as ARF), originates from the INK4/ARF or CDKN2a/b locus at human chromosome 9p21 (reviewed in Sharpless and DePinho 4 ). Expression of p16 INK4a inhibits the cell cycle, promotes cellular senescence, and has been linked to cancer and aging in mammalian systems. Expression of p16 INK4a has been shown to markedly increase with age in nearly all mammalian tissues, and caloric restriction, which retards aging in rodents, attenuates this age-induced increase in p16 INK4a . 19,20 because germline p16 INK4a -deficient mice have increased thymocyte and peripheral T-cell numbers. 21,22 Of particular importance to the present work, we and others have shown an accumulation of p16 INK4a expressing T cells in human peripheral blood with aging. 17,23 This expression of p16 INK4a appears to be a biomarker of physiologic as opposed to chronologic age, independently correlating with gerontogenic behaviors such as smoking and physical inactivity. 17 Although these murine and human data Submitted September 2, 2010; accepted December 9, 2010. Prepublished online as Blood First Edition paper, January 18, 2011; DOI 10.1182 DOI 10. /blood-2010 An Inside Blood analysis of this article appears at the front of this issue.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. With regard to lymphoid cancers, deletion and silencing of the INK4a/ARF locus are among the most common genetic events in a variety of human lymphoid and plasma cell malignancies, particularly pediatric B-and T-lineage acute lymphoblasti...

Expression of p16INK4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

“…The somatic loss of p16 INK4a can initiate increased cell division and cancer in a cell‐type‐specific fashion (Liu et al., 2011), leading us to investigate chondrocyte proliferation and neoplasia in this cohort. We did not observe neoplasia in the articular cartilage, but did note a high rate of medullary neoplasia accompanied by abundant intramedullary bone formation in Acan tm1(cre/ERT2)Crm p16 L/L mice (Figure S3).…”

“…The senescence biomarker p16 INK4a mediates cell cycle arrest through inhibition of cyclin‐dependent kinase 4 and 6 (CDK4/6), but p16 INK4a expression is not required for production of the SASP (Coppe et al., 2011). Furthermore, in vivo evidence suggests that the primary functional consequence of high p16 INK4a expression with aging is to limit the proliferation of specific cell types during homeostasis or in response to injury (Janzen et al., 2006; Krishnamurthy et al., 2006; Liu et al., 2011; Molofsky et al., 2006; Sousa‐Victor et al., 2014). Several groups, however, have suggested cell cycle independent effects of p16 INK4a and CDK4/6 inhibition (Goel et al., 2017; Murakami, Mizoguchi, Saito, Miyasaka & Kohsaka, 2012), and it is unclear whether reduced p16 INK4a expression can protect tissues from age‐related pathologies that are associated with the SASP but not with replicative failure.…”

Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner

“…Furthermore, the lack of effect of p16 deletion cannot be attributed to compensation by Arf, because HSCs from irradiated Arf and p16/Arf KO mice exhibited changes similar to those seen in the cells from WT mice after TBI. The finding that IR induced HSC senescence and residual BM suppression in a p16 and Arf-independent manner is intriguing, because upregulation of p16 and Arf has been implicated in mediating induction of HSC senescence in a variety of pathological conditions and during aging, 8,41,42 and it has been shown that IR induced senescence in BM stromal cells in a p16-and Arf-dependent manner. 32 Furthermore, early T-lymphoid progenitors are exquisitely dependent on CDK4/6 activity and, therefore, are very sensitive to p16 upregulation for induction of senescence during aging.…”

p16INK4A – Connecting Cell Cycle Control to Cell Death Regulation in Human Leukemia

“…Interestingly, the animals mainly suffered from tumors that manifested in the central nervous system but still expressed CD45 leukocyte-common antigen. These tumor cells were negative for a neuromeningeal marker, proving that they are not brain tumors and expressed B-lymphocyte markers demonstrating their B-cell origin (Liu et al, 2011). In this paper the authors argued therefore that in the T-cell linage p16INK4A merely regulates cell senescence in the mouse, whereas in the B-cell lineage loss of p16INK4A contributes to lymphoid cancer.…”