The tumor suppressor p16Ink4a regulates T lymphocyte survival

Bianchi, Teresa; Rufer, Nathalie; MacDonald, H. Robson; Migliaccio, Marianna

doi:10.1038/sj.onc.1209437

Cited by 26 publications

(20 citation statements)

References 30 publications

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“…Immune cells modulate obesityinduced glucose intolerance and insulin resistance in T2D. p16 INK4a and p15 INK4b modulate T lymphocyte proliferation, senescence, and apoptosis [59][60][61]. In myeloid cells, p15 INK4b plays a role in monocyte proliferation [62].…”

Section: Cdkn2a/b and Chronic Inflammation In Diabetes And Obesitymentioning

confidence: 99%

Functional genomics of the CDKN2A/B locus in cardiovascular and metabolic disease: what have we learned from GWASs?

Hannou

Wouters

Paumelle

et al. 2015

Trends in Endocrinology & Metabolism

143

122

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Section: Cdkn2a/b and Chronic Inflammation In Diabetes And Obesitymentioning

confidence: 99%

Functional genomics of the CDKN2A/B locus in cardiovascular and metabolic disease: what have we learned from GWASs?

Hannou

Wouters

Paumelle

et al. 2015

Trends in Endocrinology & Metabolism

143

122

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“…18 Consistent with this result, a role for p16 INK4a in peripheral T-cell replicative senescence/hypoproliferation has been proposed 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.…”

Section: Introductionmentioning

confidence: 99%

Expression of p16INK4a prevents cancer and promotes aging in lymphocytes

Liu¹,

Johnson²,

Fedoriw

et al. 2011

Blood

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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...

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“…[12][13][14] Evidence from loss-and gain-of-function studies indicates that Ink4a is an important regulator of thymopoiesis. For example, thymus size is increased in Ink4a-deficient mouse strains, 15,16 and mice engineered to express Ink4a under the control of an lck promoter have a block in T-cell differentiation at the DN3 stage. 17 More recently, Liu et al conditionally deleted Ink4a in thymocytes by mating mice with a floxed Ink4a allele to lck-Cre mice and demonstrated that thymic involution was delayed significantly.…”

Section: Introductionmentioning

confidence: 99%

Fibroblast growth factor-7 partially reverses murine thymocyte progenitor aging by repression of Ink4a

Berent-Maoz

Montecino‐Rodriguez

Signer

et al. 2012

Blood

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Involution of the thymus results in reduced production of naive T cells, and this in turn is thought to contribute to impaired immunity in the elderly. Early T-cell progenitors (ETPs), the most immature intrathymic Tcell precursors, harvested from the involuted thymus exhibit a diminished proliferative potential and increased rate of apoptosis and as a result their number is significantly reduced. In the present study, we show that these age-induced alterations result in part from increased expression of the Ink4a tumor-suppressor gene in ETPs. We also show that repression of Ink4a in aged ETPs results in their partial rejuvenation and that this can be accomplished by in vivo fibroblast growth factor 7 administration. These results define a genetic basis for thymocyte progenitor aging and demonstrate that the senescence-associated gene Ink4a can be pharmacologically repressed in ETPs to partially reverse the effects of aging. (Blood. 2012;119(24):5715-5721) IntroductionT-cell development in the thymus is a highly regulated process in which immature, BM derived progenitors progress through various intermediate stages before generating mature T lymphocytes. 1,2 Early T-cell progenitors (ETPs), defined by their lineage-negative (Lin Ϫ ) CD44 ϩ CD25 Ϫ CD117(c-kit) high phenotype, 3 are thought to be the most immature intrathymic population. ETPs in turn differentiate into the double-negative (DN) progeny DN2, DN3, and DN4 in which TCR rearrangements occur. The latter cells then generate CD4 ϩ CD8 ϩ double-positive thymocytes that mature into CD4 ϩ or CD8 ϩ single-positive T lymphocytes.Declines in thymopoiesis can result from various physiologic and pathologic processes, and this may ultimately contribute to immunodeficiency and increased susceptibility to life-threatening infections. For example, a hallmark of immune system aging is involution of the thymus, resulting in a reduced production of naive T cells that has been proposed to underlie, at least in part, the impaired immunity observed in the elderly. 4,5 The causes of thymus involution are multifactorial and complex, 6 but the effects are manifest in 2 distinct cellular compartments. First, it is known that thymic epithelial cells that constitute a key element of the thymus microenvironment decline in number with age. 7 In addition, the number of ETPs in the aged thymus is significantly reduced because of their diminished proliferative potential and increased rate of apoptosis. 8,9 A decline in proliferation is a hallmark of stem and progenitor cell aging in multiple tissues, and recent studies have implicated the p16 Ink4a and p19 Arf tumor-suppressor proteins, which are encoded by the Cdkn2a locus, in this process. 10,11 Expression of Ink4a results in activation of retinoblastoma, which in turn leads to inhibition of cell-cycle progression, and p19 Arf promotes the activity of p53, which induces cell-cycle arrest and/or apoptosis. [12][13][14] Evidence from loss-and gain-of-function studies indicates that Ink4a is an important regulator of thymopoiesis. Fo...

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The tumor suppressor p16Ink4a regulates T lymphocyte survival

Cited by 26 publications

References 30 publications

Functional genomics of the CDKN2A/B locus in cardiovascular and metabolic disease: what have we learned from GWASs?

Functional genomics of the CDKN2A/B locus in cardiovascular and metabolic disease: what have we learned from GWASs?

Expression of p16INK4a prevents cancer and promotes aging in lymphocytes

Fibroblast growth factor-7 partially reverses murine thymocyte progenitor aging by repression of Ink4a

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