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Inducible pRb2/p130 Expression and Growth-suppressive Mechanisms: Evidence of a pRb2/p130, p27^Kip1, and Cyclin E Negative Feedback Regulatory Loop¹

Department of Pathology, Anatomy & Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania, 19107 [C. M. H., P. P. C., P. S., F. P. J., N. M. S., A. G.]; Department of Scienze Odontostomatologiche e Maxillo Facciali, Universita’ degli Studi di Napoli "Federico II", Naples, Italy [P. P. C.]; Laboratory for Cell Metabolism and Pharmacokinetics, Center for Experimental Research, Regina Elena Institute, 00158 Rome, Italy [A. D. L.]; Istituto di malattie dell’apparato respiratorio, II Universita’ degli Studi di Napoli, Istituto di Ricerca Cardio-Pneumologico A.O. "Monaldi," Napoli, Italy [M. C.]; and Center for NeuroVirology and NeuroOncology, MCP-Hahnemann University, Philadelphia, Pennsylvania 19102 [K. K.]

The retinoblastoma family of proteins, pRb/p105, p107, and pRb2/p130, cooperate to regulate cell cycle progression through the G₁ phase of the cell cycle. Each of the family members realize their common goal of G₁-S checkpoint regulation through overlapping and unique growth regulatory pathways. We took advantage of a tetracycline-regulated gene expression system to control the expression of RB2/p130 in JC virus-induced hamster brain tumor cells to study in vivo the molecular mechanisms used by pRb2/p130 to elicit its growth-suppressive function. We have previously used this system to demonstrate that induction of pRb/p130 expression suppresses tumor growth in vivo by overcoming neoplastic transformation mediated by the large T-antigen oncoprotein of JCV (JCV TAg). Here we found that induction of pRb2/p130 in vivo specifically inhibits cyclin A- and cyclin E-associated kinase activity and by doing so induces p27^Kip1 levels presumably by inhibiting p27^Kip1-targeted proteolysis by cyclin E-Cdk2 phosphorylation of p27^Kip1. RB2/p130 induction also decreased cyclin A and the transcription factor E2F-1 while increasing cyclin E at both the transcriptional and protein levels of expression. The growth inhibitory activity of pRb2/p130 also correlated with its E2F-binding capacity. Furthermore, p27^Kip1 and pRb2/p130 were found to be targets of the JCV TAg oncoprotein and to interact in vivo with each other independently from the presence of TAg. Interestingly, pRb2/p130 expression negatively modulated the binding of p27^Kip1 to JCV TAg. These data suggest that pRb2/p130 and p27^Kip1 may cooperate in regulating cellular proliferation, and both may be involved in a negative feedback regulatory loop with cyclin E.

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