PU.1 Directly Regulates cdk6 Gene Expression, Linking the Cell Proliferation and Differentiation Programs in Erythroid Cells

Arthur I. Skoultchi,Olga Ujhelly,Kevin S. Choe,Sandeep N. Wontakal

doi:10.1074/jbc.m109.077727

Abstract

Cell proliferation and differentiation are highly coordinated processes during normal development. Most leukemia cells are blocked from undergoing terminal differentiation and also exhibit uncontrolled proliferation. Dysregulated expression of transcription factor PU.1 is strongly associated with Friend virus-induced erythroleukemia. PU.1 inhibits erythroid differentiation by binding to and inhibiting GATA-1. PU.1 also may be involved in controlling proliferation of erythroid cells. We reported previously that the G(1) phase-specific cyclin-dependent kinase 6 (CDK6) also blocks erythroid differentiation. We now report that PU.1 directly stimulates transcription of the cdk6 gene in both normal erythroid progenitors and erythroleukemia cells, as well as in macrophages. We propose that PU.1 coordinates proliferation and differentiation in immature erythroid cells by inhibiting the GATA-1-mediated gene expression program and also by regulating expression of genes that control progression through the G(1) phase of the cell cycle, the period during which the decision to differentiate is made.

Highlights

GATA-1 and PU.1 are two transcription factors that play central roles in the development of several hematopoietic lineages
We reported previously that differentiation of erythroleukemia cells is accompanied by a rapid down-regulation of cyclin-dependent kinase 6 (CDK6), which parallels the decline in PU.1 [20]
CDK6 Is the Dominant D-Type CDK in Proliferating Erythroid Cells—In previous work, we showed that CDK6 is the active D-type cyclin-dependent kinase in proliferating murine erythroleukemia (MEL) blasts [20, 27]

Summary

Introduction

GATA-1 and PU.1 are two transcription factors that play central roles in the development of several hematopoietic lineages. After finding that PU.1, a transcription factor, and CDK6, a G1 phase-specific cell cycle kinase, both can block erythroid differentiation, we were prompted to ask whether PU.1 controls cdk6 gene expression.

Results

Conclusion