MOLECULAR CHARACTERIZATION OF A MEMBER OF THE RB FAMILY

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Many forms of human malignancies have been linked to mutations in the tumor suppressor gene retinoblastoma, RB. The nuclear phosphoprotein, pRb, is involved indirectly in the cell cycle machinery by serving as a negative regulator in some specific cell types through its interactions with cellular proteins such as the transcription factor E2F. The importance of pRb in the inhibition of proliferation is evidenced by the necessity of a number of oncogenic human DNA viruses to encode functional oncoproteins, which can effectively bind and sequester pRb, in order to elicit a transformed phenotype in infected cells. The interaction of pRb with the viral oncoproteins as well as to E2F occurs at a specific "pocket region" in pRb. This pocket region is shared by two additional E1A associated proteins and has lead to the identification of the Rb-family of proteins, pRb, p107 and the newest member that we have recently cloned, pRb2/ p130. Recent functional studies of p107 and pRb2/pl30 have indicated that while the Rb-family members may be able to complement each other the proteins are not fully functionally redundant. Like pRb, ectopic expression of p107 is able to suppress the growth of certain cell lines. Additionally, pRb, p107, and p130/pRb2 form complexes with E2F. However, the temporal order of the complexes formation appears to vary. There is no evidence to support the notion that p107 is normally a tumor suppressor. Furthermore, the expression of p107 in cell lines derived from retinoblastoma tumors implies that p107 is unable to complement the lack of pRb and to suppress tumor formation. pRb2/p130, however, has been mapped to human chromosome 16q12.2, an area in which deletions have been found in several human neoplasias which is in support of an involvement of the RB2/p130 gene in human cancer as a tumor suppressor gene. The goals of this proposal are thus: (1) To assess the role of pRb2/p130 in cellular proliferation and tumorigenesis. (2) To analyze Rb2/p130 during growth arrest and apoptosis either coupled or uncoupled from the developmental program of terminal differentiation. (3) To investigate the interactions of Rb2/p130 with the IGF-1 pathway with regard to transcriptional and post-transcriptional modifications. (4) To investigate the interactions of pRb2/p130 with the Myb-family genes.