Document Detail

Id3 upregulates BrdU incorporation associated with a DNA damage response, not replication, in human pancreatic β-cells.
MedLine Citation:
PMID:  21964314     Owner:  NLM     Status:  MEDLINE    
Elucidating mechanisms of cell cycle control in normally quiescent human pancreatic β-cells has the potential to impact regeneration strategies for diabetes. Previously we demonstrated that Id3, a repressor of basic Helix-Loop-Helix (bHLH) proteins, was sufficient to induce cell cycle entry in pancreatic duct cells, which are closely related to β-cells developmentally. We hypothesized that Id3 might similarly induce cell cycle entry in primary human β-cells. To test this directly, adult human β-cells were transduced with adenovirus expressing Id3. Consistent with a replicative response, β-cells exhibited BrdU incorporation. Further, Id3 potently repressed expression of the cyclin dependent kinase inhibitor p57 (Kip2 ) , a gene which is also silenced in a rare β-cell hyperproliferative disorder in infants. Surprisingly however, BrdU positive β-cells did not express the proliferation markers Ki67 and pHH3. Instead, BrdU uptake reflected a DNA damage response, as manifested by hydroxyurea incorporation, γH2AX expression, and 53BP1 subcellular relocalization. The uncoupling of BrdU uptake from replication raises a cautionary note about interpreting studies relying solely upon BrdU incorporation as evidence of β-cell proliferation. The data also establish that loss of p57 (Kip2) is not sufficient to induce cell cycle entry in adult β-cells. Moreover, the differential responses to Id3 between duct and β-cells reveal that β-cells possess intrinsic resistance to cell cycle entry not common to all quiescent epithelial cells in the adult human pancreas. The data provide a much needed comparative model for investigating the molecular basis for this resistance in order to develop a strategy for improving replication competence in β-cells.
Seung-Hee Lee; Ergeng Hao; Fred Levine; Pamela Itkin-Ansari
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-11-01
Journal Detail:
Title:  Islets     Volume:  3     ISSN:  1938-2022     ISO Abbreviation:  Islets     Publication Date:    2011 Nov-Dec
Date Detail:
Created Date:  2011-11-02     Completed Date:  2012-06-01     Revised Date:  2014-10-09    
Medline Journal Info:
Nlm Unique ID:  101495366     Medline TA:  Islets     Country:  United States    
Other Details:
Languages:  eng     Pagination:  358-66     Citation Subset:  IM    
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MeSH Terms
Bromodeoxyuridine / metabolism*
Cell Cycle / genetics,  physiology
Cell Growth Processes / genetics,  physiology
Cyclin-Dependent Kinase Inhibitor p57 / antagonists & inhibitors,  biosynthesis*,  genetics
DNA Damage*
Gene Expression Regulation
Histones / metabolism
Inhibitor of Differentiation Proteins / genetics,  metabolism*
Insulin-Secreting Cells / cytology,  metabolism*
Intracellular Signaling Peptides and Proteins / metabolism
Ki-67 Antigen / metabolism
Mice, Inbred ICR
Reg. No./Substance:
0/Cyclin-Dependent Kinase Inhibitor p57; 0/H2AFX protein, human; 0/Histones; 0/Inhibitor of Differentiation Proteins; 0/Intracellular Signaling Peptides and Proteins; 0/Ki-67 Antigen; 0/TP53BP1 protein, human; 135845-89-5/Idb3 protein, mouse; G34N38R2N1/Bromodeoxyuridine

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