The p16(INK4A) protein and flavopiridol restore yeast cell growth inhibited by Cdk4

Cyclin-dependent kinase 4 (Cdk4) activity is misregulated in most cancers. Loss of Cdk4 regulation can occur through overexpression of Cdk4 catalytic subunit or its regulatory partner cyclin D1, or if the Cdk4-specific inhibitory protein p16(INK4A) is inactive. We have attempted to express the two h...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 1998-09, Vol.250 (3), p.791-797
Main Authors: Moorthamer, M, Panchal, M, Greenhalf, W, Chaudhuri, B
Format: Article
Language:English
Subjects:
Cdk4 protein
Cyclin D1 - physiology
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase Inhibitor p16 - physiology
Cyclin-Dependent Kinases - physiology
Flavonoids
flavopiridol
Gene Expression Regulation, Fungal - physiology
Humans
p16 protein
Piperidines
Proto-Oncogene Proteins
Saccharomyces cerevisiae
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - growth & development
Signal Transduction - genetics
Transfection
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Summary:Cyclin-dependent kinase 4 (Cdk4) activity is misregulated in most cancers. Loss of Cdk4 regulation can occur through overexpression of Cdk4 catalytic subunit or its regulatory partner cyclin D1, or if the Cdk4-specific inhibitory protein p16(INK4A) is inactive. We have attempted to express the two human subunits, Cdk4 and cyclin D1, in the yeast Saccharomyces cerevisiae. Surprisingly, expression of Cdk4 alone, under control of the strong GAL promoter, inhibits cell growth. Coexpression of both subunits allows formation of an active Cdk4-cyclin D1 complex which accentuates growth arrest. In cells expressing Cdk4 only, growth is restored by overexpressing human Cdc37, a Cdk4-binding molecular chaperone. Interestingly, the effect of Cdk4 on yeast is also overcome by both p16- and p21-families of Cdk-inhibitory proteins. Moreover, flavopiridol, a compound which inhibits Cdk4 enzyme activity, restores cell division. The fact that p16(INK4A) and flavopiridol negate Cdk4-mediated suppression of yeast cell growth implies that this simple system can be used as a screen for identifying Cdk4-specific antagonists which may mimic p16(INK4A) in the cancer cell cycle.
ISSN:0006-291X
DOI:10.1006/bbrc.1998.9348