The cell cycle inhibitory protein p21cip is not essential for maintaining beta-cell cycle arrest or beta-cell function in vivo.

Abstract:

:p21(cip1), a regulatory molecule upstream of the G(1/0) checkpoint, is increased in beta-cells in response to mitogenic stimulation. Whereas p21(cip1) can variably stimulate or inhibit cell cycle progression, in vitro studies suggest that p21(cip1) acts as an inhibitor in the pancreatic beta-cell. To determine the functional role of p21(cip1) in vivo, we studied p21-null mice. Surprisingly, islet mass, beta-cell replication rates, and function were normal in p21-null mice. We next attempted to drive beta-cell replication in p21-null mice by crossing them with rat insulin II promoter-murine PL-1 (islet-targeted placental lactogen transgenic) mice. Even with this added replicative stimulus of PL, p21-null islets showed no additional stimulation. A G(1/S) proteome scan demonstrated that p21(cip1) loss was not associated with compensatory increases in other cell cycle inhibitors (pRb, p107, p130, p16, p19, and p27), although mild increases in p57 were apparent. Surprisingly, p18, which had been anticipated to increase, was markedly decreased. In summary, isolated p21(cip1) loss, as for pRb, p53, p18, and p27 and other inhibitors, results in normal beta-cell development and function, either because it is not essential or because its function is subserved or complimented by another protein. These studies underscore marked inhibitory pressure and the complexity and plasticity of inhibitory pathways that restrain beta-cell replication.

journal_name

Diabetes

journal_title

Diabetes

authors

Cozar-Castellano I,Haught M,Stewart AF

doi

10.2337/db06-0627

subject

Has Abstract

pub_date

2006-12-01 00:00:00

pages

3271-8

issue

12

eissn

0012-1797

issn

1939-327X

pii

55/12/3271

journal_volume

55

pub_type

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