Mutational inactivation of the retinoblastoma tumor suppressor gene (Rb) causes retinoblastoma and contributes to most human cancers. Rb is also required for normal embryonic development in the mouse. The long-term goals of our lab are to characterize the mechanisms utilized to effect normal Rb function, to ascertain how these mechanisms are regulated, and to determine the contribution these mechanisms make to normal function in vivo. In vitro, Rb can regulate several major cellular processes, including the cell cycle, differentiation, and apoptosis. Since naturally occurring and synthetic mutations have been discovered that affect one of these Rb-dependent functions but not others, they are likely mediated by independent mechanisms. Mutational analysis also points out that these Rb-mediated molecular mechanisms can be regulated independently by phosphorylation at different subsets of serine or threonine residues. These observations suggest that normal Rb function in vivo may require the execution and proper coordination of distinct molecular mechanisms. It is currently unclear what contribution each of these molecular mechanisms, or their proper coordination by site-specific phosphorylation, make to normal embryonic development or Rb dependent tumor suppression. We hypothesize that normal Rb function in vivo will be partially compromised by mutations that affect a single Rb-mediated mechanism, or by mutations that affect normal site-specific phosphorylation. Through phenotypic analysis of such mutant alleles in vivo, the contribution of distinct Rbmediated molecular mechanisms to embryonic development and tumor suppression can be ascertained. We propose the following aims to test the hypothesis: 1) Identify mutant alleles specifically deficient in regulation of E2F 1-dependent transcription or normal site-specific phosphorylation; 2) Characterize the molecular defect in selected Rb mutant alleles; 3) Create and characterize mouse Rb mutant alleles analogous to selected human mutant alleles identified in aims 1-2; 4) Generate mice containing selected mutant Rb alleles; 5) Confirm the molecular deficiency of select mutant alleles in vivo; 6) Characterize the phenotype of mice containing mutant Rb alleles.
| Ku, Sheng Yu; Rosario, Spencer; Wang, Yanqing et al. (2017) Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355:78-83 |
| 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 |
| Yang, Jun; Li, Yanping; Khoury, Thaer et al. (2008) Relationships of hHpr1/p84/Thoc1 expression to clinicopathologic characteristics and prognosis in non-small cell lung cancer. Ann Clin Lab Sci 38:105-12 |
| 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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