The expression of retinoblastoma and Sp1 is increased by low concentrations of cyclin-dependent kinase inhibitors.

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Penuelas S, Alemany C, Noe V, Ciudad CJ

The expression of retinoblastoma and Sp1 is increased by low concentrations of cyclin-dependent kinase inhibitors.

Eur J Biochem. 2003 Dec;270(24):4809-22.

PubMed ID

14653808 [ View in PubMed

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Abstract

We examined the effect of suboptimal concentrations of cyclin-dependent kinase inhibitors, which do not interfere with cell proliferation, on retinoblastoma expression in hamster (Chinese hamster ovary K1) and human (K562 and HeLa) cells. To achieve this, we used the chemical inhibitors roscovitine and olomoucine (which inhibit CDK2 preferentially), UCN-01 (which also inhibits CDK4/6) and p21 (as an intrinsic inhibitor). All chemical inhibitors and overexpression of p21 strongly induced retinoblastoma protein expression. UCN-01-mediated retinoblastoma expression was caused by an increase in both the levels of retinoblastoma mRNA and the stability of the protein. The expression of the transcription factor Sp1, a retinoblastoma-interacting protein, was also enhanced by all the cyclin-dependent kinase inhibitors tested. However, Sp1 expression was caused by an increase in the levels of Sp1 mRNA without modification in the stability of the protein. By using luciferase experiments, the transcriptional activation of both retinoblastoma and Sp1 promoters by UCN-01 was confirmed. Bisindolylmaleimide I, at concentrations causing a similar or higher inhibition of protein kinase C than UCN-01, provoked a lower activation of retinoblastoma and Sp1 expression. Finally, the effects of cyclin-dependent kinase inhibitors on dihydrofolate reductase gene expression were evaluated. Treatment with UCN-01 increased cellular dihydrofolate reductase mRNA levels, and dihydrofolate reductase enzymatic activity was enhanced by UCN-01, roscovitine, olomoucine and p21, in transient transfection experiments. These results support a mechanism for the self-regulation of retinoblastoma expression, and point to the need to establish the appropriate dose of cyclin-dependent kinase inhibitors as antiproliferative agents in anticancer treatments.

DrugBank Data that Cites this Article

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
7-Hydroxystaurosporine	Experimental Investigational	RB1	5925	upregulated	7-hydroxystaurosporine results in increased expression of RB1 mRNA	13q14.2
7-Hydroxystaurosporine	Experimental Investigational	SP1	6667	upregulated	7-hydroxystaurosporine results in increased expression of SP1 mRNA	12q13.13
Olomoucine	Experimental	RB1	5925	upregulated	olomoucine results in increased expression of RB1 mRNA	13q14.2
Olomoucine	Experimental	SP1	6667	upregulated	olomoucine results in increased expression of SP1 mRNA	12q13.13