Document Detail


The CDK4/6 inhibitor PD0332991 reverses epithelial dysplasia associated with abnormal activation of the cyclin-CDK-Rb pathway.
MedLine Citation:
PMID:  22508966     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Loss of normal growth control is a hallmark of cancer progression. Therefore, understanding the early mechanisms of normal growth regulation and the changes that occur during preneoplasia may provide insights of both diagnostic and therapeutic importance. Models of dysplasia that help elucidate the mechanisms responsible for disease progression are useful in highlighting potential targets for prevention. An important strategy in cancer prevention treatment programs is to reduce hyperplasia and dysplasia. This study identified abnormal upregulation of cell cycle-related proteins cyclin D1, cyclin-dependent kinase (CDK)4, CDK6, and phosphorylated retinoblastoma protein (pRb) as mechanisms responsible for maintenance of hyperplasia and dysplasia following downregulation of the initiating viral oncoprotein Simian virus 40 (SV40) T antigen. Significantly, p53 was not required for successful reversal of hyperplasia and dysplasia. Ligand-induced activation of retinoid X receptor and PPARγ agonists attenuated cyclin D1 and CDK6 but not CDK4 or phosphorylated pRb upregulation with limited reversal of hyperplasia and dysplasia. PD0332991, an orally available CDK4/6 inhibitor, was able to prevent upregulation of cyclin D1 and CDK6 as well as CDK4 and phosphorylated pRb and this correlated with a more profound reversal of hyperplasia and dysplasia. In summary, the study distinguished CDK4 and phosphorylated pRb as targets for chemoprevention regimens targeting reversal of hyperplasia and dysplasia.
Authors:
M Carla Cabrera; Edgar S Díaz-Cruz; Bhaskar V S Kallakury; Michael J Pishvaian; Clinton J Grubbs; Donald D Muccio; Priscilla A Furth
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-04-16
Journal Detail:
Title:  Cancer prevention research (Philadelphia, Pa.)     Volume:  5     ISSN:  1940-6215     ISO Abbreviation:  Cancer Prev Res (Phila)     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-06-05     Completed Date:  2012-11-23     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  101479409     Medline TA:  Cancer Prev Res (Phila)     Country:  United States    
Other Details:
Languages:  eng     Pagination:  810-21     Citation Subset:  IM    
Copyright Information:
©2012 AACR.
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MeSH Terms
Descriptor/Qualifier:
Animals
Blotting, Western
Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
Cyclins / genetics,  metabolism*
Epithelial Cells / pathology*
Humans
Immunoenzyme Techniques
Male
Mice
Mice, Transgenic
Phosphorylation
Piperazines / pharmacology*
Pyridines / pharmacology*
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Retinoblastoma Protein / genetics,  metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Tumor Suppressor Protein p53 / physiology*
Grant Support
ID/Acronym/Agency:
2R01 CA89041-1OS1/CA/NCI NIH HHS; 5P30CA051008/CA/NCI NIH HHS; G20 RR025828-01/RR/NCRR NIH HHS; IG20 RR025828-01/RR/NCRR NIH HHS; P30 CA051008/CA/NCI NIH HHS; P30 CA051008-17/CA/NCI NIH HHS; P30 CA051008-18/CA/NCI NIH HHS; P30 CA051008-19/CA/NCI NIH HHS; R01 CA089041/CA/NCI NIH HHS; R01 CA089041-05/CA/NCI NIH HHS; R01 CA089041-06/CA/NCI NIH HHS; R01 CA089041-08/CA/NCI NIH HHS; R01 CA089041-09/CA/NCI NIH HHS; R01 CA089041-10/CA/NCI NIH HHS; R01 CA089041-10S1/CA/NCI NIH HHS; R01 CA112176/CA/NCI NIH HHS; R01 CA112176/CA/NCI NIH HHS; R01 CA112176-01/CA/NCI NIH HHS; R01 CA112176-02/CA/NCI NIH HHS; R01 CA112176-03/CA/NCI NIH HHS; R01 CA112176-04/CA/NCI NIH HHS; R01 CA112176-05/CA/NCI NIH HHS; T32 CA009686/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-ylpyridin-2-ylamino)-8H-pyrido(2,3-d)pyrimidin-7-one; 0/Cyclins; 0/Piperazines; 0/Pyridines; 0/RNA, Messenger; 0/Retinoblastoma Protein; 0/Tumor Suppressor Protein p53; EC 2.7.11.22/Cyclin-Dependent Kinase 4; EC 2.7.11.22/Cyclin-Dependent Kinase 6
Comments/Corrections

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