p16INK4a induces an age-dependent decline in islet regenerative potential

@article{Krishnamurthy2006p16INK4aIA,
  title={p16INK4a induces an age-dependent decline in islet regenerative potential},
  author={Janakiraman Krishnamurthy and Matthew R. Ramsey and Keith L. Ligon and Chad D. Torrice and A. Koh and Susan Bonner-Weir and Norman E Sharpless},
  journal={Nature},
  year={2006},
  volume={443},
  pages={453-457}
}
The p16INK4a tumour suppressor accumulates in many tissues as a function of advancing age. p16INK4a is an effector of senescence and a potent inhibitor of the proliferative kinase Cdk4 (ref. 6), which is essential for pancreatic β-cell proliferation in adult mammals. Here we show that p16INK4a constrains islet proliferation and regeneration in an age-dependent manner. Expression of the p16INK4a transcript is enriched in purified islets compared with the exocrine pancreas, and islet-specific… Expand

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References

SHOWING 1-10 OF 37 REFERENCES
Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing
TLDR
Declining subventricular zone progenitor function and olfactory bulb neurogenesis during ageing are caused partly by increasing p16INK4a expression, which encodes a cyclin-dependent kinase inhibitor linked to senescence. Expand
Ink4a/Arf expression is a biomarker of aging.
The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examinedExpand
Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis
TLDR
The generation and characterization of a p16Ink4a-specific knockout mouse that retains normal p19Arf function are described, establishing that p 16Ink 4a, along with p19 Arf, functions as a tumour suppressor in mice. Expand
Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice
TLDR
It is shown that p27Kip1 progressively accumulates in the nucleus of pancreatic beta cells in mice that lack either insulin receptor substrate 2 or the long form of the leptin receptor, and represents a potential new target for the treatment of this condition. Expand
In vivo proliferation of differentiated pancreatic islet beta cells in transgenic mice expressing mutated cyclin-dependent kinase 4
TLDR
Activated CDK4 stimulates postnatal pancreatic beta cell proliferation, during which the highly differentiated phenotypes of pancreatic islet beta cells are preserved without malignant transformation. Expand
Significant Role for p16INK4a in p53-Independent Telomere-Directed Senescence
TLDR
It is concluded that p16(INK4a) contributes to the p53-independent response to telomere damage. Expand
Genetic Evidence for Functional Dependency of p18Ink4c on Cdk4
TLDR
Genetic evidence is provided that in mice p18 Ink4c and p27 Kip1 mediate the transduction of different cell growth and proliferation signals to CDK4 and that p18 ink4c is functionally dependent onCDK4. Expand
Cyclins D2 and D1 Are Essential for Postnatal Pancreatic β-Cell Growth
TLDR
It is shown that cyclins D2 and D1 are essential for normal postnatal islet growth in adult mice, and strategies to tightly regulate D-type cyclin activity in β cells could prevent or cure diabetes. Expand
Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a
TLDR
It is reported that the cyclin-dependent kinase inhibitor p16INK4a accumulates and modulates specific age-associated HSC functions, and may ameliorate the physiological impact of ageing on stem cells and thereby improve injury repair in aged tissue. Expand
Accelerated telomere shortening and senescence in human pancreatic islet cells stimulated to divide in vitro.
TLDR
It is indicated that cellular senescence is responsible for limiting the number of cell divisions that human beta-cells can undergo, and this results have implications for the use of primary human islet cells in cell transplantation therapies for diabetes. Expand
...
1
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