Document Detail

Induction of beta-cell proliferation and retinoblastoma protein phosphorylation in rat and human islets using adenovirus-mediated transfer of cyclin-dependent kinase-4 and cyclin D1.
MedLine Citation:
PMID:  14693709     Owner:  NLM     Status:  MEDLINE    
The major regulator of the gap-1/synthesis phase (G(1)/S) cell cycle checkpoint is the retinoblastoma protein (pRb), and this is regulated in part by the activities of cyclin-dependent kinase (cdk)-4 and the D cyclins. Surprisingly, given the potential importance of beta-cell replication for islet replacement therapy, pRb presence, phosphorylation status, and function have not been explored in beta-cells. Here, adenoviruses expressing cdk-4 and cyclin D(1) were used to explore rat and human pRb phosphorylation and beta-cell cycle control. pRb is present in rat and human islets, and overexpression of cyclin D(1)/cdk-4 led to strikingly enhanced pRb phosphorylation in both species. Combined overexpression of both cdk-4 and cyclin D(1) caused a threefold increase in [(3)H]thymidine incorporation. This increase in proliferation was confirmed independently using insulin and bromodeoxyuridine immunohistochemistry, where human beta-cell replication rates were increased 10-fold. Cdk-4 or cyclin D(1) overexpression did not adversely effect beta-cell differentiation or function. The key cell cycle regulatory protein, pRb, can be harnessed to advantage using cyclin D(1)/cdk-4 for the induction of human and rodent beta-cell replication, enhancing replication without adversely affecting function or differentiation. This approach will allow detailed molecular study of the cellular mechanisms regulating the cell cycle in beta-cells, beta-cell lines, and stem cell-derived beta-cells.
Irene Cozar-Castellano; Karen K Takane; Rita Bottino; A N Balamurugan; Andrew F Stewart
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Diabetes     Volume:  53     ISSN:  0012-1797     ISO Abbreviation:  Diabetes     Publication Date:  2004 Jan 
Date Detail:
Created Date:  2003-12-24     Completed Date:  2004-02-27     Revised Date:  2012-06-25    
Medline Journal Info:
Nlm Unique ID:  0372763     Medline TA:  Diabetes     Country:  United States    
Other Details:
Languages:  eng     Pagination:  149-59     Citation Subset:  AIM; IM    
Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
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MeSH Terms
Adenoviridae / genetics*
Base Sequence
Cell Division
Cells, Cultured
Cyclin D1 / genetics,  metabolism*
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinases / genetics,  metabolism*
DNA Primers
Islets of Langerhans / cytology*,  metabolism*
Proto-Oncogene Proteins*
Recombinant Proteins / metabolism
Retinoblastoma Protein / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Grant Support
Reg. No./Substance:
0/DNA Primers; 0/Proto-Oncogene Proteins; 0/Recombinant Proteins; 0/Retinoblastoma Protein; 136601-57-5/Cyclin D1; EC protein, human; EC protein, rat; EC Kinase 4; EC Kinases

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