The retinoblastoma susceptibility gene (RB1) was one of the first tumor suppressor genes to be discovered and it has long served as prototype for this group of cancer-associated genes. Mutation of RB1 is the rate-limiting event in the development of the childhood cancer, retinoblastoma, and the RB1 gene product (pRb) is absent or misregulated in over 90% of human cancers. Mammalian cells contain three Rb-family members and homologous genes have been conserved during the evolution of both plants and animals. pRB binds to transcription factors and recruits chromatin modifying enzymes to promoters. pRB family members are believed to co-ordinate global changes in gene expression programs during cell cycle exit, allowing cells to switch off genes that are needed for cell proliferation and switch on genes that are needed for differentiation. How pRB family members orchestrate these changes is unclear. In the previous cycle of this grant we discovered a new activity of pRB-family proteins. We found that they physically interact with CAP-D3 a component of Condensin II complexes. Condensin complexes are conserved from yeast to humans and are required for normal chromosome structure during mitosis. Experiments using the Drosophila model system show that dCAP-D3 is extremely important for RBF1 function. We hypothesize that dCAP-D3 and Condensin II complexes have functions in addition to their well-studied roles during mitosis. We propose that Condensin II complexes are recruited to specific locations in the genome by pRB family proteins and that, at those sites, they act in conjunction with pRB family proteins to regulate levels of gene expression. To test this, we will identify genes regulated by dCAP-D3/Condensin II and RBF1. We will generate interaction-defective alleles to test the hypothesis that RBF1 and dCAP-D3 provide an element of transcriptional regulation that is distinct from its interactions with E2F. Using biochemical approaches we will purify RBF1/dCAP-D3 complexes and will examine the mechanisms underlying the functional co-operation between dCAP-D3 and RBF1.
Cancer is one of the leading causes of mortality in the United States. This proposal investigates the normal function of the retinoblastoma protein, pRB, one of the most famous and best characterized tumor suppressors. These experiments test the hypothesis that the localized action of pRB-family proteins at individual promoters is coupled, through an interaction with Condensin II complexes, to a more extensive organization of chromosomal domains.
|Weng, Daniel Y; Chen, Jinguo; Taslim, Cenny et al. (2016) Persistent alterations of gene expression profiling of human peripheral blood mononuclear cells from smokers. Mol Carcinog 55:1424-37|
|Song, Min-Ae; Marian, Catalin; Brasky, Theodore M et al. (2016) Chemical and toxicological characteristics of conventional and low-TSNA moist snuff tobacco products. Toxicol Lett 245:68-77|
|Miles, Wayne O; Lepesant, Julie M J; Bourdeaux, Jessie et al. (2015) The LSD1 Family of Histone Demethylases and the Pumilio Posttranscriptional Repressor Function in a Complex Regulatory Feedback Loop. Mol Cell Biol 35:4199-211|
|Miles, Wayne O; Korenjak, Michael; Griffiths, Lyra M et al. (2014) Post-transcriptional gene expression control by NANOS is up-regulated and functionally important in pRb-deficient cells. EMBO J 33:2201-15|
|Korenjak, Michael; Kwon, Eunjeong; Morris, Robert T et al. (2014) dREAM co-operates with insulator-binding proteins and regulates expression at divergently paired genes. Nucleic Acids Res 42:8939-53|
|Hsu, Ping-Ching; Zhou, Bin; Zhao, Yi et al. (2013) Feasibility of identifying the tobacco-related global metabolome in blood by UPLC-QTOF-MS. J Proteome Res 12:679-91|
|Stepanov, Irina; Muzic, John; Le, Chap T et al. (2013) Analysis of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing DNA adducts in human exfoliated oral mucosa cells by liquid chromatography-electrospray ionization-tandem mass spectrometry. Chem Res Toxicol 26:37-45|
|Herr, Anabel; Longworth, Michelle; Ji, Jun-Yuan et al. (2012) Identification of E2F target genes that are rate limiting for dE2F1-dependent cell proliferation. Dev Dyn 241:1695-707|
|Nicolay, Brandon N; Dyson, Nicholas J (2012) It's all in the timing: too much E2F is a bad thing. PLoS Genet 8:e1002909|
|Rees, Vaughan W; Kreslake, Jennifer M; Wayne, Geoffrey Ferris et al. (2012) Role of cigarette sensory cues in modifying puffing topography. Drug Alcohol Depend 124:1-10|
Showing the most recent 10 out of 42 publications