Increased gene dosage of<i>Ink4a/Arf</i>results in cancer resistance and normal aging

Matheu, Ander; Pantoja, Cristina; Efeyan, Alejo; Criado, Luis M.; Juan, Manel; Flores, Juana M.; Klatt, Peter; Serrano, Manuel

doi:10.1101/gad.310304

Cited by 126 publications

(129 citation statements)

References 40 publications

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“…This raises the question of whether these increases in p16 Ink4a and p19 Arf expression cause age-related declines in tissue function (Sharpless 2004). Although moderately increased expression of p16 Ink4a and p19 Arf in transgenic mice did not detectably accelerate aging or change life span (Matheu et al 2004), the increase in p16 Ink4a and p19 Arf expression in these mice was small relative to the increase observed in old mice. The levels of p16 Ink4a and p19 Arf that are required to promote aging may be qualitatively higher than the levels that are required to inhibit cancer.…”

Section: The Ink4a Tumor Suppressor May Also Promote Stem Cell Agingmentioning

confidence: 69%

Stem Cell Self-Renewal and Cancer Cell Proliferation Are Regulated by Common Networks That Balance the Activation of Proto-oncogenes and Tumor Suppressors

Pardal¹,

Molofsky²,

He³

et al. 2005

Cold Spring Harbor Symposia on Quantitative Biology

126

101

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Section: The Ink4a Tumor Suppressor May Also Promote Stem Cell Agingmentioning

confidence: 69%

Stem Cell Self-Renewal and Cancer Cell Proliferation Are Regulated by Common Networks That Balance the Activation of Proto-oncogenes and Tumor Suppressors

Pardal¹,

Molofsky²,

He³

et al. 2005

Cold Spring Harbor Symposia on Quantitative Biology

126

101

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“…The dynamic regulation of the INK4a/b locus is of tremendous importance to tumorigenesis (32)(33)(34)(35)(36), stem-cell maintenance (9,13), cellular senescence (37), and systemic aging (19,38). Here, we have demonstrated that naked mole rat cells express a novel INK4 isoform, pALT INK4a/b , composed of the first exon of p15 INK4b and the second and third exons of p16 INK4a (Fig.…”

Section: Discussionmentioning

confidence: 92%

INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform

Tian

Azpurua

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The naked mole rat (Heterocephalus glaber) is a long-lived and tumor-resistant rodent. Tumor resistance in the naked mole rat is mediated by the extracellular matrix component hyaluronan of very high molecular weight (HMW-HA). HMW-HA triggers hypersensitivity of naked mole rat cells to contact inhibition, which is associated with induction of the INK4 (inhibitors of cyclin dependent kinase 4) locus leading to cell-cycle arrest. The INK4a/b locus is among the most frequently mutated in human cancer. This locus encodes three distinct tumor suppressors: p15 INK4b , p16 INK4a , and ARF (alternate reading frame). Although p15 INK4b has its own ORF, p16 INK4a and ARF share common second and third exons with alternative reading frames. Here, we show that, in the naked mole rat, the INK4a/b locus encodes an additional product that consists of p15 INK4b exon 1 joined to p16 INK4a exons 2 and 3. We have named this isoform pALT INK4a/b (for alternative splicing). We show that pALT INK4a/b is present in both cultured cells and naked mole rat tissues but is absent in human and mouse cells. Additionally, we demonstrate that pALT INK4a/b expression is induced during early contact inhibition and upon a variety of stresses such as UV, gamma irradiation-induced senescence, loss of substrate attachment, and expression of oncogenes. When overexpressed in naked mole rat or human cells, pALT INK4a/b has stronger ability to induce cell-cycle arrest than either p15 INK4b or p16 INK4a . We hypothesize that the presence of the fourth product, pALT INK4a/b of the INK4a/b locus in the naked mole rat, contributes to the increased resistance to tumorigenesis of this species.naked mole rat | INK4 | p16 | p15

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“…The s-p53 mice showed significant decrease in ROS generation and DNA damage. The super-Arf (s-Arf) transgenic mice were generated using a similar method [43]. Since Arf stabilizes p53, dual transgenic Arf/p53 mice were generated by crossing s-Arf and s-p53 mice to study the combined effects of both genes [44].…”

Section: P53 Mouse Modelsmentioning

confidence: 99%

Models of reactive oxygen species in cancer

Ogasawara

Huang

2007

Drug Discovery Today: Disease Models

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Increased generation of reactive oxygen species (ROS) has been observed in cancer, degenerative diseases, and other pathological conditions. ROS can stimulate cell proliferation, promote genetic instability, and induce adaptive responses that enable cancer cells to maintain their malignant phenotypes. However, when cellular redox balance is severely disturbed, high levels of ROS may cause various damages leading to cell death. The studies of ROS effects on biological systems, their underlying mechanisms and therapeutic implications largely depend on proper experimental models. Here we review several in vitro and in vivo models for ROS research.

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Increased gene dosage ofInk4a/Arfresults in cancer resistance and normal aging

Cited by 126 publications

References 40 publications

Stem Cell Self-Renewal and Cancer Cell Proliferation Are Regulated by Common Networks That Balance the Activation of Proto-oncogenes and Tumor Suppressors

Stem Cell Self-Renewal and Cancer Cell Proliferation Are Regulated by Common Networks That Balance the Activation of Proto-oncogenes and Tumor Suppressors

INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform

Models of reactive oxygen species in cancer

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