CONTROL OF RETINOBLASTOMA PROTEIN-INDEPENDENT HEMATOPOIETIC-CELL CYCLE BY THE PRB-RELATED P130

The retinoblastoma tumor suppressor protein (pRB) is a potent inhibito r of mammalian cell growth and the functional inactivation of pRB is w idely presumed to be essential for progression of the cell cycle from G(1) phase. In this work, the generality of pRB-based cell cycle contr ol in mammalian cells was addressed by conditionally expressing PRE in cytokine-dependent hematopoietic cells. We show herein that these cel ls are able to progress through the cell cycle in response to cytokine despite the continued presence of supraphysiological amounts of wild- type pRB or phosphorylation-resistant pRB mutants. However, their grow th was strongly blocked by ectopic expression of the pRB-related pocke t protein, p130. This growth inhibition required the E2F-binding pocke t domain but not the cyclin-binding domain of p130, Furthermore, incre ased amounts of the p130-controlled E2F, termed E2F-4, potentiated the mitogenic response of the cells to cytokine and the constitutive over expression of E2F-4 rendered the cells cytokine-independent Our result s indicate the existence of a non-pRB-based cell cycle whose operation depends primarily on the interplay between p130 and E2F-4 in certain hematopoietic cells.