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Dominant role of CDKN2B/p15INK4B of 9p21.3 tumor suppressor hub in inhibition of cell-cycle and glycolysis
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Dominant role of CDKN2B/p15INK4B of 9p21.3 tumor suppressor hub in inhibition of cell-cycle and glycolysis
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Journal Article
Dominant role of CDKN2B/p15INK4B of 9p21.3 tumor suppressor hub in inhibition of cell-cycle and glycolysis
2021
Overview
Human chromosome 9p21.3 is susceptible to inactivation in cell immortalization and diseases, such as cancer, coronary artery disease and type-2 diabetes. Although this locus encodes three cyclin-dependent kinase (CDK) inhibitors (p15
INK4B
, p14
ARF
and p16
INK4A
), our understanding of their functions and modes of action is limited to the latter two. Here, we show that in vitro p15
INK4B
is markedly stronger than p16
INK4A
in inhibiting pRb1 phosphorylation, E2F activity and cell-cycle progression. In mice, urothelial cells expressing oncogenic
HRas
and lacking p15
INK4B
, but not those expressing
HRas
and lacking p16
INK4A
, develop early-onset bladder tumors. The potency of CDKN2B/p15
INK4B
in tumor suppression relies on its strong binding via key N-terminal residues to and inhibition of CDK4/CDK6. p15
INK4B
also binds and inhibits enolase-1, a glycolytic enzyme upregulated in most cancer types. Our results highlight the dual inhibition of p15
INK4B
on cell proliferation, and unveil mechanisms whereby p15
INK4B
aberrations may underpin cancer and non-cancer conditions.
The human chromosome locus 9p21.3 is a tumour suppressor hub which encodes three CDK inhibitors, p15INK4B, p14ARF and p16INK4A. Here, the authors show that p15INK4B inhibits the cell cycle and glycolysis in a murine model of HRas + ‐mediated urothelial carcinoma and has a more relevant role as a tumour suppressor than its neighbouring p16INK4A.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 13/31
/ 13/44
/ 13/51
/ 13/89
/ 14/63
/ 64/60
/ 82/1
/ 82/47
/ Age
/ Animals
/ Bladder
/ Breeding
/ Cancer
/ Chromosomes, Mammalian - genetics
/ Cyclin-Dependent Kinase Inhibitor p15 - chemistry
/ Cyclin-Dependent Kinase Inhibitor p15 - metabolism
/ Cyclin-Dependent Kinase Inhibitor p16 - metabolism
/ Cyclin-Dependent Kinases - metabolism
/ Female
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Loci
/ Male
/ Phosphopyruvate Hydratase - metabolism
/ Proto-Oncogene Proteins p21(ras)
/ Science
/ Structural Homology, Protein
/ Tumors
