Abstract:
:Diabetes (T1DM and T2DM) is characterized by a deficit in β-cell mass. A broader understanding of human β-cell replication mechanism is thus important to increase β-cell proliferation for future therapeutic interventions. Here, we show that p27 (Kip1), a CDK inhibitor, is expressed abundantly in isolated adult human islets and interacts with various positive cell cycle regulatory proteins including D-type cyclins (D1, D2 and D3) and their kinase partners, CDK4 and CDK6. Also, we see interaction of cyclin E and its kinase partner, CDK2, with p27 suggesting a critical role of p27 as a negative cell cycle regulator in human islets. Our data demonstrate interaction of p27 with GSK-3 in β-cells and show, employing rodent β-cells (INS-1), isolated human islets and purified β-cells derived from human islets, that siRNA-mediated depletion of GSK-3 or p27 or 1-AKP / BIO - mediated GSK-3 inhibition results in increased β-cell proliferation. We also see reduction of p27 levels following GSK-3 inactivation or depletion. Our data show that serum induction of quiescent INS-1 cells leads to sequential phosphorylation of p27 on its S10 and T187 residues with faster kinetics for S10 corresponding with the decreased levels of p27. Altogether our findings indicate that p27 levels in β-cells are stabilized by GSK-3 and thus p27 down regulation following GSK-3 depletion / inactivation plays a critical role in promoting β-cell replication.
journal_name
Isletsjournal_title
Isletsauthors
Stein J,Milewski WM,Hara M,Steiner DF,Dey Adoi
10.4161/isl.3.1.14435subject
Has Abstractpub_date
2011-01-01 00:00:00pages
21-34issue
1eissn
1938-2014issn
1938-2022pii
14435journal_volume
3pub_type
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