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Blocking a Cell Cycle Inhibitor Stimulates Replication of Insulin-Producing Beta Cells

By BiotechDaily International staff writers
Posted on 27 Jan 2014
Image: Replicating human beta cells. In cells where p57 was successfully inhibited, beta cells could undergo DNA replication. Pink: nucleus that has undergone DNA replication. Green: Insulin. Blue: Nuclei counterstained for DNA. White: p57 (Photo courtesy of Dr. Klaus Kaestner, University of Pennsylvania).
Image: Replicating human beta cells. In cells where p57 was successfully inhibited, beta cells could undergo DNA replication. Pink: nucleus that has undergone DNA replication. Green: Insulin. Blue: Nuclei counterstained for DNA. White: p57 (Photo courtesy of Dr. Klaus Kaestner, University of Pennsylvania).
Diabetes researchers have found that they could stimulate replication of mature pancreatic beta cells by blocking the activity of the cell cycle inhibitor protein p57Kip2.

The CDKN1C gene encodes the protein p57Kip2, which is a potent tight-binding inhibitor of several G1 cyclin/CDK complexes (cyclin E-CDK2, cyclin D2-CDK4, and cyclin A-CDK2) and, to lesser extent, of the mitotic cyclin B-CDC2. It is a negative regulator of cell proliferation and may play a role in the maintenance of the nonproliferative state throughout life. It is expressed in the heart, brain, lung, skeletal muscle, kidney, pancreas, and testis.

Investigators at the University of Pennsylvania (Philadelphia, USA) and their colleagues at the Hebrew University of Jerusalem (Israel) used short hairpin RNA (shRNA) to suppress the CDKN1C gene in human beta cells obtained from deceased adult donors.

They reported in the January 16, 2014, online edition of the Journal of Clinical Investigation that when human pancreatic tissue with inhibited p57Kip2 activity was transplanted into hyperglycemic, immunodeficient mice, beta cell replication increased more than three-fold. The newly replicated cells retained properties of mature beta cells, including the expression of beta cell markers such as insulin, PDX1, and NKX6.1. Furthermore, these newly replicated cells demonstrated normal glucose-induced calcium influx, further indicating beta cell functionality.

These results showed that beta cells from older humans, in which baseline replication is negligible, could be coaxed to reenter and complete the cell cycle while maintaining mature beta cell properties. Controlled manipulation of this pathway holds promise for the expansion of beta cells in patients with type II diabetes.

Related Links:

University of Pennsylvania
Hebrew University of Jerusalem



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