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- Title
Induction of β-Cell Proliferation and Retinoblastoma Protein Phosphorylation in Rat and Human Islets Using Adenovirus-Mediated Transfer of Cyclin-Dependent Kinase-4 and Cyclin D[sub1].
- Authors
Cozar-Castellano, Irene; Takane, Karen K.; Stewart, Andrew F.; Bottino, Rita; Balamurugan, A. N.
- Abstract
The major regulator of the gap-1/synthesis phase (G[sub 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 β-cell replication for islet replacement therapy, pRb presence, phosphorylation status, and function have not been explored in β-cells. Here, adenoviruses expressing cdk-4 and cyclin D[sub 1] were used to explore rat and human pRb phosphorylation and β-cell cycle control, pRb is present in rat and human islets, and overexpression of cyclin D[sub 1]/cdk-4 led to strikingly enhanced pRb phosphorylation in both species. Combined overexpression of both cdk-4 and cyclin D[sub 1] caused a threefold increase in [³H]thymidine incorporation. This increase in proliferation was confirmed independently using insulin and bromodeoxyuridine immunohistochemistry, where human β-cell replication rates were increased 10-fold. Cdk-4 or cyclin D[sub 1] overexpression did not adversely effect β-cell differentiation or function. The key cell cycle regulatory protein, pRb, can be harnessed to advantage using cyclin D[sub 1]/cdk-4 for the induction of human and rodent β-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 β-cells, β-cell lines, and stem cell-derived β-cells.
- Subjects
PANCREATIC beta cells; RETINOBLASTOMA; PHOSPHORYLATION; ISLANDS of Langerhans; ADENOVIRUSES; CYCLIN-dependent kinases
- Publication
Diabetes, 2004, Vol 53, Issue 1, p149
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/diabetes.53.1.149