Retinoblastoma gene product (pRB) plays critical roles in regulation of the cell cycle and tumor suppression. It is known that downregulation of pRB can stimulate carcinogenesis via abrogation of the pRB pathway, although the mechanism has not been elucidated. In this study, we found that Mdm2, a ubiquitin ligase for p53, promoted ubiquitin-dependent degradation of pRB. pRB was efficiently ubiq...

Inactivation of the retinoblastoma gene produd (pRb) occurs concomitant with the appearance of its hyperphosphorylated form in mid to late G1 . Multiple cyclin/CDK complexes are implicated in the cell cycle phosphorylation of pRb. Using in vivo expression systems, we show that cyclins A, E, , D2, and D3 each function to phosphorylate and inactivate pRb. In vivo, Gi cyclin/kinase complexes enhan...

The liver exhibits an exquisitely controlled cell cycle, wherein hepatocytes are maintained in quiescence until stimulated to proliferate. The retinoblastoma tumor suppressor, pRB, plays a central role in proliferative control by inhibiting inappropriate cell cycle entry. In many cases, liver cancer arises due to aberrant cycles of proliferation, and correspondingly, pRB is functionally inactiv...

The retinoblastoma susceptibility protein (pRB) is a phosphoprotein that regulates cell cycle progression at the G1/S transition. In quiescent and early G1 cells, pRB predominantly exists in the active hypophosphorylated form. The cyclin/cyclin-dependent protein kinase complexes phosphorylate pRB at the late G1 phase to inactivate pRB. This event leads to the dissociation and activation of E2F ...

The retinoblastoma protein (pRb) is a cell cycle regulator inactivated in most human cancers. Loss of pRb function results from mutations in the gene coding for pRb or for any of its upstream regulators. Although pRb is predominantly known as a cell cycle repressor, our data point to additional pRb functions in cell adhesion. Our data show that pRb regulates the expression of a wide repertoire ...

The functions of the retinoblastoma protein (pRb) are in part regulated by reversible and cell cycle-dependent phosphorylation. While the regulation of pRb by cyclin-dependent kinases (Cdks) has been studied extensively, the role(s) of protein phosphatase 1 (PP1) in controlling pRb are only partially understood. In this chapter, we will describe experimental approaches to investigate the intera...

Previous investigations have suggested that probenecid (PRB) alters the in vivo disposition of valproic acid (VPA), perhaps by inhibiting hepatic formation of valproate glucuronide (VG). Because VPA and PRB bind moderately to plasma proteins, protein binding also is a potential locus of interaction. The purpose of this investigation was to determine whether in vitro systems could accurately pre...

We have developed a yeast model system to address transcriptional repression by the retinoblastoma protein (pRB). When fused to the DNA-binding domain of Gal4p (DB-pRB), pRB can repress transcription of reporter genes containing Gal4p binding sites; the histone deacetylase activity encoded by yeast RPD3 is required for DB-pRB repression. Mutation of the LXCXE binding cleft in pRB, a region repo...

The retinoblastoma tumor-suppressor protein (pRb) is known to induce growth arrest and cellular differentiation. The molecular determinants of pRb function include protein-protein interactions and post-translational modifications such as phosphorylation. Recently, the co-activator p300 was found to acetylate pRb. The biological significance of pRb acetylation, however, remains unclear. In the p...

The retinoblastoma tumor suppressor protein (pRB) plays a critical role in the control of cell proliferation and in the DNA damage checkpoints. pRB inhibits cell cycle progression through interactions with the E2F family of transcription factors. Here, we report that DNA damage induced not only the dephosphorylation of pRB at Cdk phosphorylation sites and the binding of pRB to E2F-1, but also t...