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• W2011691982 abstract "Purpose/Objective: Hallmark features of leukemias and many other cancers include both uncontrolled proliferation and a block to terminal differentiation. Although tremendous progress has been made in elucidating the molecular mechanisms of tumorigenesis, still very little is known about the relationship between proliferation and the block to differentiation in tumor cells. Using in vitro differentiation of murine erythroleukemia (MEL) cells, which can be forced to reenter terminal erythroid differentiation, we explored the relationship between cell cycle regulators and a hematopoietic-specific transcription factor, PU.1, which is activated in erythroleukemias and blocks erythroid differentiation. Materials/Methods: During the reentry of MEL cells to terminal differentiation, it was shown that the levels of PU.1 and cyclin dependent kinase 6 (CDK6) are coordinately down regulated, and that constitutive expression of either protein can block MEL cells from differentiating. Utilizing in vitro kinase assays and two-dimensional electrophoresis, the ability of CDK6 to phosphorylate PU.1 was examined. Deletion mutants of PU.1 were used as substrates in in vitro kinase assays to map potential phosphorylation sites. The biological function of PU.1 phosphorylation was also studied, including the effects on protein stability and transcriptional activity. In addition, to address whether CDK6 is a transcriptional target gene of PU.1, CDK6 mRNA levels were measured in MEL cells inducibly expressing PU.1. To investigate the regulation of CDK6 transcription by PU.1, various CDK6 promotor fragments were analyzed for activation by PU.1 in luciferase reporter assays. Results: We show that there exists a regulatory loop, coupling PU.1 and CDK6, which potentiates the oncogenic activity of both proteins. First, we show that PU.1 is a novel substrate of CDK6 both in vitro and in vivo. Immunoprecipitated CDK6 was able to phosphorylate bacterially purified PU.1 in in vitro kinase assays. When deletion mutants of PU.1 were used in in vitro kinase assays, the results showed that all three of the predicted CDK phosphorylation sites (T99, S126, and S142) were indeed phosphorylated by CDK6. In vivo, inducible expression of CDK6 in MEL cells led to an increase in hyperphosphorylated forms of PU.1 as demonstrated by two-dimensional electrophoresis. Phosphorylation of PU.1 by CDK6 results in increased amounts of PU.1 protein, presumably due to increased protein stability. Whereas CDK6 phosphorylates PU.1 leading to increased amounts of PU.1 protein, PU.1, in turn, activates CDK6 transcription. When exogenous PU.1 was inducibly expressed in MEL cells, there was a rapid and dramatic increase in CDK6 mRNA level. CDK6 promotor deletion studies indicate that responsiveness of the promotor to PU.1 lies within a 200 bp fragment upstream of the transcriptional start site. Conclusions: We provide evidence for a regulatory loop connecting CDK6, a cell cycle activator, and PU.1, a transcription factor which blocks erythroid differentiation. The results demonstrate a molecular mechanism linking proliferation and the block to differentiation in tumor cells. Since the most important effects of radiation on mammalian cells are cell cycle arrest and terminal differentiation, illuminating the relationship between these two processes in tumor cells will enhance our understanding of cellular response to radiation therapy." @default.
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• W2011691982 date "2002-10-01" @default.
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• W2011691982 title "Linking proliferation and the block to differentiation in leukemia: a potential regulatory loop between PU.1 and CDK6" @default.
• W2011691982 doi "https://doi.org/10.1016/s0360-3016(02)03427-2" @default.
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