Regulation of Cell Cycle Progression

Our laboratory is interested in the signaling pathways which regulate the entry and progression of cell cycle. We also have a developing interest in epigenetics with a special emphasis on histone methylation.

We use molecular biology, biochemical approaches, and mouse genetics to decipher molecular mechanisms of 1) how cells are programmed and reprogrammed to properly respond to internal and external stresses; 2) how dysregulation of these processes reflect the pathogenesis of human diseases including cancer; and 3) how the established genetic and epigenetic information is inherited to daughter cells.

To achieve these goals we are currently investigating several aspects of the regulatory pathways. Firstly, we are studying the p53 signaling pathway, which is essential for cell cycle arrest and apoptotic induction upon numerous stresses. We have recently identified Bat3 as a novel positive regulator of p53 transactivation in DNA damage response. We are in the process of investigating the biological activity, tissue specific functions, and interacting molecules of Bat3. Interestingly, Bat3 has been reported to act as a positive regulator of H3K4 methylation (a critical histone modification for transcriptional activity), and is required for BRCA1 expression. In addition, cancer cell lines and human tissue samples with Bat3 mutations and polymorphisms are identified.

Secondly, we are focusing on histone demethylases, of which gain and loss have been identified in numerous human cancers including breast cancer. We have created mouse models and cell lines to investigate biological functions of these genes. We are currently testing whether the loss or gain of specific demethylase has any impact on tumorigenesis and tumor suppression in vivo and in vitro.

Since regulatory mechanisms of these pathways touch on many topics of key interests in biology and are anticipated to have far-reaching implications for medicine and the understanding of the basic processes of cell fate determination, the resulting outcomes will undoubtedly form an important knowledge base of human diseases.

For additional information, please visit http://www.uhnres.utoronto.ca/researchers/profile.php?lookup=4528

Graduate Students:

• Rashi Gupta

Selected References:

• HLA-B-associated transcript 3 (Bat3/Scythe) negatively regulates Smad phosphorylation in BMP signaling (2011). Goto K, Tong KI, Ikura J, Okada H. Cell Death Dis. 2:e236. doi: 10.1038/cddis.2011.114.
• Kawazu M, Saso K, Tong KI, McQuire T, Goto K, Wakeham A, Miyagishi M, Mat TW, Okada H. (2011) Histone Demethylase JMJD2B Functions as a Co-Factor of Estrogen Receptor in Breast Cancer Proliferation and Mammary Gland Development. PLoS ONE 6(3): e17830.
• Sasaki T, Marcon E, McQuire T, Arai Y, Moens PB, Okada H. (2008): Bat3 deficiency accelerates the degradation of Hsp70-2/HspA2 during spermatogenesis. J. Cell Biol. 182 (3):449-458.
• asaki, T., Gan, E., Wakeham, A., Kornbluth, S., Mak, TW., Okada, H. (2007): HLA-B-associated transcript 3(Bat3)/Scythe is Essential for p300-mediated Acetylation of p53. GenesDev. 21(7):848-61.
• ronzo, L., Okada, H., Pasolli, HA., Wakeham, A., Itie, You-Ten A., Mak, TW., Fuchs, E. (2005): Sgk3 Links Growth Factor Signaling to Maintenance of Progenitor Cells in the Hair Follicle. J. Cell Biol. 170 (4):559-570.
• kada, H. and Mak, T.W. (2004): Pathways of Apoptotic and Non-Apoptotic Death in Cancer Nat. Rev. Cancer 4(8):592-603.