Document Detail


Identification of small-molecule inducers of pancreatic beta-cell expansion.
MedLine Citation:
PMID:  19164755     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
To identify small molecules that can induce beta-cell replication, a large chemical library was screened for proliferation of growth-arrested, reversibly immortalized mouse beta cells by using an automated high-throughput screening platform. A number of structurally diverse, active compounds were identified, including phorbol esters, which likely act through protein kinase C, and a group of thiophene-pyrimidines that stimulate beta-cell proliferation by activating the Wnt signaling pathway. A group of dihydropyridine (DHP) derivatives was also shown to reversibly induce beta-cell replication in vitro by activating L-type calcium channels (LTCCs). Our data suggest that the LTCC agonist 2a affects the expression of genes involved in cell cycle progression and cellular proliferation. Furthermore, treatment of beta cells with both LTCC agonist 2a and the Glp-1 receptor agonist Exendin-4 showed an additive effect on beta-cell replication. The identification of small molecules that induce beta-cell proliferation suggests that it may be possible to reversibly expand other quiescent cells to overcome deficits associated with degenerative and/or autoimmune diseases.
Authors:
Weidong Wang; John R Walker; Xia Wang; Matthew S Tremblay; Jae Wook Lee; Xu Wu; Peter G Schultz
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-01-22
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  106     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2009 Feb 
Date Detail:
Created Date:  2009-02-04     Completed Date:  2009-02-27     Revised Date:  2013-03-19    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1427-32     Citation Subset:  IM    
Affiliation:
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Data Bank Information
Bank Name/Acc. No.:
GEO/GSE12802
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium Channel Agonists / pharmacology*
Calcium Channels, L-Type / drug effects
Cell Line, Transformed
Cell Proliferation / drug effects*
Dihydropyridines / pharmacology
Islets of Langerhans / cytology,  drug effects*,  metabolism
Mice
Oligonucleotide Array Sequence Analysis
Peptides / pharmacology
Receptors, Glucagon / agonists
Reverse Transcriptase Polymerase Chain Reaction
Venoms / pharmacology
Wnt Proteins / agonists
Chemical
Reg. No./Substance:
0/Calcium Channel Agonists; 0/Calcium Channels, L-Type; 0/Dihydropyridines; 0/Peptides; 0/Receptors, Glucagon; 0/Venoms; 0/Wnt Proteins; 0/glucagon-like peptide-1 receptor; 141732-76-5/exenatide
Comments/Corrections
Erratum In:
Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7264

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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