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

Lingwen Zhong, Senta Georgia, Shuen Ing Tschen, Keiko Nakayama, Keiichi Nakayama, Anil Bhushan

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Diabetes results from an inadequate mass of functional β cells, due to either β cell loss caused by immune assault or the lack of compensation to overcome insulin resistance. Elucidating the mechanisms that regulate β cell mass has important ramifications for fostering β 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 β cell proliferation. In Skp2-/- mice, accumulation of p27 resulted in enlarged polyploid β cells as a result of endoreduplication replacing proliferation. Despite β cell hypertrophy, Skp2-/- mice exhibited diminished β cell mass, hypoinsulinemia, and glucose intolerance. Increased insulin resistance resulting from diet-induced obesity caused Skp2-/- mice to become overtly diabetic, because β 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 β cell mass and to respond to increased metabolic demand associated with insulin resistance.

Original languageEnglish
Pages (from-to)2869-2876
Number of pages8
JournalJournal of Clinical Investigation
Volume117
Issue number10
DOIs
Publication statusPublished - Oct 1 2007
Externally publishedYes

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Growth
Insulin Resistance
Endoreduplication
Polyploidy
Foster Home Care
Glucose Intolerance
Ligases
Ubiquitin
Cell Division
Hypertrophy
Regeneration
Obesity
Cell Proliferation
Diet
Therapeutics

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic β cells. / Zhong, Lingwen; Georgia, Senta; Tschen, Shuen Ing; Nakayama, Keiko; Nakayama, Keiichi; Bhushan, Anil.

In: Journal of Clinical Investigation, Vol. 117, No. 10, 01.10.2007, p. 2869-2876.

Research output: Contribution to journalArticle

Zhong, Lingwen ; Georgia, Senta ; Tschen, Shuen Ing ; Nakayama, Keiko ; Nakayama, Keiichi ; Bhushan, Anil. / Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic β cells. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 10. pp. 2869-2876.
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