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Oncogene. 1997 Dec 4;15(23):2855-66.

Engineered mutants of pRB with improved growth suppression potential.

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Canji Inc., San Diego, California 92121, USA.


We have constructed a panel of substitution mutants which affect one or more of the putative cdk target sites of the RB protein. We have examined the activity of these mutants relative to wild-type RB by both a transcriptional repression assay and by measuring growth suppression in vitro. We find that some phosphorylation site mutants of pRB can repress E2 transcription more strongly than wild-type RB. These mutants are partially resistant to phosphorylation by cdks and can arrest tumor cells in G1 in vitro. Our results indicate a functional correlation between the ability to repress E2F-dependent transcription and the ability to suppress tumor cell growth in vitro. In addition, we describe two classes of RB mutants: N-terminal truncated p56RB and a novel mutant of RB containing multiple substitutions near its nuclear localization signal. Both classes of RB mutants have greater activity than the wild-type protein. Because RB is a key regulator of cell cycle progression, expression of a more potent, phosphorylation resistant RB may have utility in both RB(-/-) and RB(+/+) tumors as well as in hyperproliferative disorders.

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