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PMID: 17823659 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic beta cells.

The Journal of clinical investigation ·Vol. 117 ·No. 10 ·2007-10-00 ·Pages 2869-76

Zhong L, Georgia S, Tschen SI, Nakayama K, Nakayama K, Bhushan A

Abstract

Diabetes results from an inadequate mass of functional beta cells, due to either beta cell loss caused by immune assault or the lack of compensation to overcome insulin resistance. Elucidating the mechanisms that regulate beta cell mass has important ramifications for fostering beta cell regeneration and the treatment of diabetes. We report here that Skp2, a substrate recognition component of Skp1-Cul1-F-box (SCF) ubiquitin ligase, played an essential and specific role in regulating the cellular abundance of p27 and was a critical determinant of beta cell proliferation. In Skp2(-/-) mice, accumulation of p27 resulted in enlarged polyploid beta cells as a result of endoreduplication replacing proliferation. Despite beta cell hypertrophy, Skp2(-/-) mice exhibited diminished beta cell mass, hypoinsulinemia, and glucose intolerance. Increased insulin resistance resulting from diet-induced obesity caused Skp2(-/-) mice to become overtly diabetic, because beta cell growth in the absence of cell division was insufficient to compensate for increased metabolic demand. These results indicate that the Skp2-mediated degradation pathway regulating the cellular degradation of p27 is essential for establishing beta cell mass and to respond to increased metabolic demand associated with insulin resistance.

MeSH Terms
Animals Cell Proliferation Cyclin-Dependent Kinase Inhibitor p27/metabolism Gene Deletion Glucose/metabolism Insulin/blood Insulin Resistance/genetics Insulin-Secreting Cells/cytology,enzymology,physiology Mice Mice, Mutant Strains Polyploidy S-Phase Kinase-Associated Proteins/genetics,physiology
Chemicals
Insulin S-Phase Kinase-Associated Proteins Cyclin-Dependent Kinase Inhibitor p27 Glucose
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Zhong Lingwen
Larry Hillblom Islet Research Center and Molecular Biology Institute, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
Georgia Senta
Tschen Shuen-Ing
Nakayama Keiko
Nakayama Keiichi
Bhushan Anil
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI32198
Published
2007-10-00
Pages
2869-76
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1964513
Subset
IM
Grants
NIDDK NIH HHS · R01 DK068763 · United States
NIGMS NIH HHS · T32 GM007185 · United States
NIDDK NIH HHS · R01 DK-068763 · United States
External Links
PubMed source DOI: 10.1172/JCI32198 PMC Full Text View journal details
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