Article

Functional analysis of Rb2/p130 interaction with cyclins

Department of Microbiology-Immunology, Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Cancer Research (Impact Factor: 9.28). 06/1996; 56(9):2003-8.
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ABSTRACT The retinoblastoma (Rb) family consists of the tumor suppressor pRb and related proteins p107 and pRb2/p130. Ectopic expression of pRb and p107 results in a growth arrest of sensitive cells in the G1 phase of the cell cycle. We demonstrated here that the growth-suppressive properties of pRb2/p130 were also specific for the G1 phase. The A-, E-, and D-type cyclins as well as transcription factor E2F1 and the E1A viral oncoprotein were able to rescue the pRb2/p130-mediated G1 growth arrest in SAOS-2 cells. The rescue with cyclins A and E correlated with their physical interaction with pRb2/p130, which surprisingly has been found to occur over all phases of the cell cycle. The phosphorylation status as well as the kinase activity associated with pRb2/p130 dramatically increased near the G1-S-phase transition. This suggests that, like the other Rb family members, pRb and p107, the phosphorylation of pRb2/p130 is controlled by the cell cycle machinery and that pRb2/p130 may indeed be another key G1-S-phase regulator.

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    • "Indeed, it has been described that p130 undergoes phosphorylation at distinctive sites during the G0 phase in a way that characterizes p130 from the other members of the Rb family proteins (Kiess et al., 1995; Canhoto et al., 2000). p130 is phosphorylated by the Cdk4/Cyclin D or Cdk6/Cyclin D and Cdk2/Cyclin E or Cdk2/Cyclin A complexes and its expression levels fall when the cells enter into the S phase (Baldi et al., 1995; Mayol et al., 1995; Claudio et al., 1996; Dong et al., 1998; Tedesco et al., 2002). In vivo phosphorylation mapping of human p130 identified 22 serine and threonine residues, targeted by the kinases Cdk2, Cdk4 and Cdk6 (Hansen et al., 2001). "
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    • "They share the ability to recruit chromatin-remodeling enzymes and their best characterized targets are the members of the E2F/DP family of transcription factors, generally referred to as E2F (Cinti et al., 2005; Tosi et al., 2005; Genovese et al., 2006; Macaluso et al., 2006; Purev et al., 2006). Both pRb2/p130 and p107 are able to bind cdk2/ cyclins A and E (Claudio et al., 1996). We have previously described the cdk2-dependent kinase inhibitory activity shown by the pRb2/p130 spacer domain, which suggests that part of its growth regulatory function could be mediated by the inhibition of this important cell cycle kinase (De Luca et al., 1997). "
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    • "Because of this, it is reasonable that pocket proteins, even overexpressed, could be extensively phosphorylated by specific cyclinicdk complexes, thus becoming functionally inactive in blocking the cell cycle. Conversely, pRb2/p130, which has been found coupled to cdk2 [Hannon et al., 1993; Claudio et al., 19961 could overcome p161NK4A homozygous deletion, bringing about effective growth inhibition. "
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