Dataset Information

Phosphorylation-resistant Rb knockin mice develop diabetes that can be attenuated by vitamin C

ABSTRACT: While the effect of phosphorylation of the tumor suppressor pRB on cell cycle progression has been analyzed extensively in vitro, little is known about the consequences of blocking the phosphorylation of endogenous pRB on development and homeostasis. Here we show that homozygous RbΔK4 and RbΔK7 knockin mice, with Ser/Thr-to-Ala substitutions in four or all seven CDK sites in the C-terminus of pRb, undergo normal embryogenesis and early development. This is despite inhibition of pRb phosphorylation on additional but not all other upstream sites. Remarkably, adult RbΔK7 but not RbΔK4 mice are smaller than control littermates and exhibit hallmarks of accelerated aging including short telomeres, infertility, kyphosis and diabetes.Diabetes is insulin-sensitive and associated with failure of quiescent pancreatic -cells to re-enter the cell cycle in response to mitogens, leading to induction of DNA damage response (DDR), senescence-associated secretory phenotype, and diminished islet mass. The epigenetic regulator vitamin C decreased pancreatic islet DDR, increased cell cycle re-entry, and attenuated diabetes in RbΔK7 mice. These results have direct implications for cell-cycle regulation, anti-CDK therapy, diabetes and longevity.

ORGANISM(S): Mus musculus

PROVIDER: GSE180507 | GEO | 2021/12/16

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Pancreatic islet transplantation as a cure for type 1 diabetes (T1D) cannot be scaled up due to a scarcity of human pancreas donors. In vitro expansion of beta cells from mature human pancreatic islets provides an alternative source of insulin-producing cells. The exact nature of the expanded cells produced by diverse expansion protocols, and their potential for differentiation into functional beta cells, remain elusive. We performed a large-scale meta-analysis of gene expression in human pancreatic islet cells, which were processed using three different previously described protocols for expansion and attempted re-differentiation. All three expansion protocols induced dramatic changes in the expression profiles of pancreatic islets; many of these changes are shared among the three protocols. Attempts at re-differentiation of expanded cells induce a limited number of gene expression changes. Nevertheless, these fail to restore a pancreatic islet-like gene expression pattern. Comparison with a collection of public microarray datasets confirmed that expanded cells are highly comparable to mesenchymal stem cells. Genes induced in expanded cells are also enriched for targets of transcription factors important for pluripotency induction. The present data increases our understanding of the active pathways in expanded and re-differentiated islets. Knowledge of the mesenchymal stem cell potential may help development of drug therapeutics to restore beta cell mass in T1D patients. Experiment Overall Design: In this study, we have tested three different protocols to expand human pancreatic islets in monolayer and after attempted maneuvers to re-differentiate the expanded cells back to islets. We have characterized the resulting cells in detail by performing microarray analyses with fresh pancreatic islets, expanded islet cells and re-differentiated cells. Genes modified by either of three protocols have 70 to 80% overlap with the genes changed by the other two protocols. Although there are promising changes in the right direction, none of the three protocols could achieve a return to a functional islet state. The expanded cells highly resemble Mesenchymal Stem Cells (MSC), and similar gene regulatory networks seem to be active in both cell types. On the other hand, the expanded islet cells are different from MSC in that they seem to retain activity of some islet gene modules. The current results highlight the importance of designing new strategies that take into account the MSC potential of expanded cells.

Dataset Information

Phosphorylation-resistant Rb knockin mice develop diabetes that can be attenuated by vitamin C

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure