pRb2/pl30: from the mechanisms to therapy. The retinoblastoma (RB) family proteins are negative cell-cycle regulators normally expressed in a number of adult tissues. Each RB protein binds to and modulates the activity of the E2F transcription factors that stimulate the transcription of genes needed to progress through the S phase. The RBs-E2Fs repressive complexes function in association with histone deacetylase (HDAC 1) which essentially repress transcription probably through deacetylation of histone tail that protrudes from nucleosome. The protein stability and the functional activity of each RB family protein can be hampered by gene silencing due to their promoter hypermethylation and/or by their post-translational modifications such as acetylation and phosphorylation. Although some indications are available about the role of epigenetic or post-translational control of pRb/pl05 functional activity, there are very few data about the other members of RB family. However, acetylation and phosphorylation may be not completely independent processes. Phosphorylation and acetylation status can influence also the protein stability by determining the probability of ubiquitin-mediated degradation, which it is though to be an early event in programmed cell death, possibly related to cell commitment to apoptosis. As a consequence, it has been shown that failure to the interior cleavage of pRb/p105 is associates with resistance to induction of apoptotic response. Up to now no similar data has been reported for pRb2/pl30. Deregulated cell proliferation together with suppressed apoptosis, constitute the minimal common platform upon which all neoplastic evolution occurs. The rationale for these studies is that the identification of significance of the epigenetic or post-translational modification on the function, stability, biochemical interactions and degradation of pRb2/pl30. We will pursue the following aims:/) Rb2/p130 negatively regulates the transcription of cell-cycle genes to exert its growth suppressive function. 2) Epigenetic events for pRb2/p130 gene silencing promoting tumor progression. 3) pRb2/pl30 post-translational modification during the induction of growth arrest and apoptotic response. 4) The cross talk between the pRb2/pl 30 growth suppressive and apoptotic function and the activated KRas oncogenic signals in the LSL-K-Ras G12D mouse model. These experiments will provide further insight into the post-translational modifications necessary to induce pRb2/p 130- dependent growth suppression and apoptosis. Finally, our results will be significant in that they will give us clues to the mechanisms underlying pRb2/p 130 activity and to characterize its role in tumorigenesis providing useful tools for design novel therapeutic strategies.
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