Mutation of the retinoblastoma tumor suppressor gene (Rb1) causes the pediatric cancer retinoblastoma and contributes to most types of human cancer. Despite its central role in tumorigenesis, therapies designed to target this pathway have been slow to develop. A detailed understanding of the molecular mechanisms underlying Rb1 mediated tumor suppression will facilitate the development of such therapies. The long-term goal of this continuing project is to identify and characterize these molecular mechanisms. Rb1 protein (pRb) is a negative regulator of the cell cycle, and this cell cycle regulatory activity contributes to tumor suppression. Multiple mechanisms likely contribute to pRb mediated cell cycle control, including the well characterized mechanism involving binding of pRb to E2F transcription factors resulting in transcriptional repression of genes required for cell cycle progression. Another possible mechanism involves targeted degradation of Skp2 by pRb and consequent stabilization of p27Kip1. The ability of pRb to regulate E2F transcription factors is genetically separable from its ability to degrade Skp2. We hypothesize that pRb mediated degradation of Skp2 and stabilization of p27Kip1 contributes to prostate tumor suppression in vivo. Our working model is that post translational stabilization of p27Kip1 (p27) normally enforces a senescence like response to oncogenic stress, thereby curtailing tumor initiation and progression. In the absence of pRb, this tumor suppressive response is muted. The goal of this application is to test the hypothesis using in vitro and in vivo experimental model systems. We have created a mouse strain containing a mutant Rb1 allele (R654W) whose encoded protein is deficient for E2F binding and regulation, but may be competent to target Skp2 for degradation. We propose to use this mutant allele to assess the relative contribution of the pRb/E2F and pRb/p27 mechanisms to prostate tumor suppression in vivo.
Two specific aims are proposed: 1) Test whether R654W pRb can suppress prostate tumorigenesis in the mouse;2) Characterize the contribution of the pRb/Skp2/p27 mechanism to R654W pRb tumor suppressor activity. Successful completion of these specific aims will identify a new mechanism contributing to Rb1 tumor suppression and suggest new therapeutic strategies to treat prostate cancer.
In order to design more effective therapies to treat cancer, we have to understand the molecular alterations that cause cancer. Loss of the retinoblastoma tumor suppressor gene (Rb1) causes the human pediatric eye tumor retinoblastoma, and it is deregulated in the majority of human adult cancers. This makes Rb1 an attractive target for therapeutic intervention. The goal of the continuing work proposed here is to understand in molecular detail how Rb1 normally functions to suppress cancer. This will facilitate the development of therapeutic strategies to target this centrally important tumor suppressor gene for the benefit of cancer patients.
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| Chinnam, Meenalakshmi; Wang, Xiaoling; Zhang, Xiaojing et al. (2016) Evaluating Effects of Hypomorphic Thoc1 Alleles on Embryonic Development in Rb1 Null Mice. Mol Cell Biol 36:1621-7 |
| Ko, Hyun-Kyung; Akakura, Shin; Peresie, Jennifer et al. (2014) A transgenic mouse model for early prostate metastasis to lymph nodes. Cancer Res 74:945-53 |
| Sun, Huifang; Wang, Yanqing; Chinnam, Meenalakshmi et al. (2011) E2f binding-deficient Rb1 protein suppresses prostate tumor progression in vivo. Proc Natl Acad Sci U S A 108:704-9 |
| Chinnam, Meenalakshmi; Goodrich, David W (2011) RB1, development, and cancer. Curr Top Dev Biol 94:129-69 |
| Xiao, Hai; Zhang, Xiaojing; Goodrich, David W (2010) Construction of a dual affinity tagged allele of the Rb1 tumor suppressor gene in the mouse. Genesis 48:121-6 |
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| Li, Yanping; Lin, Athena W; Zhang, Xiaojing et al. (2007) Cancer cells and normal cells differ in their requirements for Thoc1. Cancer Res 67:6657-64 |
| Wang, Xiaoling; Li, Yanping; Zhang, Xiaojing et al. (2007) An allelic series for studying the mouse Thoc1 gene. Genesis 45:32-7 |
| Wang, Xiaoling; Chang, Yanjie; Li, Yanping et al. (2006) Thoc1/Hpr1/p84 is essential for early embryonic development in the mouse. Mol Cell Biol 26:4362-7 |
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