MODULATION OF PRB2/P130 MEDIATED GROWTH SUPPRESSION

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The retinoblastoma gene family currently consists of three members: pRb, p107, and pRb2/p130, that share a particular functional domain termed the "pocket" structure. The pocket region is responsible for many of the known specific functionality relevant protein-protein interactions in which these molecules are involved. All three family members have been shown to be growth suppressive nuclear phosphoproteins whose phosphorylation status is regulated in a cell cycle dependent manner. Ectopic expression of each of the family members leads to G1-growth arrest of sensitive cells. The importance of the Rb family in the inhibition of proliferation is evidence by the necessity of a number of oncogenic human DNA viruses to encode oncoproteins (E1A, T-antigen, and E7) which can effectively bind and sequester the Rb-family members to elicit a transformed phenotype in infected cells. The human Prb2/p130 gene maps to 16q12.2, a region found deleted in several human neoplasia. pRb2/p130 has been implicated in the pathogenesis and progression of several human cancers, including lung cancer, suggesting that the pRb2/p130 gene may be a tumor suppressor gene like RB. Despite their many similarities, however, it is becoming increasingly clear that even though the Rb family members may be able to complement each other, they are not fully functionally redundant. Each of the Rb family members associate with and modulate the function of distinct members of the E2F transcription factor family in a temporally modulated schedule. The T98G human glioblastoma cell line is refractory to the effects of pRb and p107 but undergoes growth arrest from pR2/p130, indicating the pRb2/p130 is not merely a surrogate for either pRb or p107 and that there are fundamental differences in the specific mechanisms of growth inhibition employed by the three family members. Additionally, unlike pRb, the phosphorylated form of pRb2/p130 is the preferred target of the DNA tumor viral oncoprotein E1A, suggesting that a different mechanism may underlie the functional regulation of pRb2/p130 and demonstrating that one can not use the Rb model to speculate the significance and regulation of phosphorylation of pRb2/p130. The goals of this proposal are thus: a. To define the growth inhibitory mechanism(s) employed by pRb2/p130, b. To understand the regulatory function of pRb2/p130 phosphorylation, c. To define the role of the Rb2/p130 gene in human lung cancer development and progression, d. To prepare viral models for studying pRB2/p130 in vivo.