Dr. Pradip Raychaudhuri
- PhD, Albert Einstein College of Medicine
- Postdoctoral, Duke University
DNA Damage Response, Tumorigenesis, Metastasis
My lab is interested in the cell cycle regulators (both positive and negative) that are involved in oncogenesis and tumor suppression. Currently, we are studying the roles of the cell cycle transcription factor FoxM1 in tumor development and tumor metastasis. Also, we are studying DDB2, which was identified as a DNA repair protein, to investigate how it participates in the pathways of DNA damage response and premature senescence.
FoxM1 in oncogenesis and metastasis: FoxM1 is important for the expression of several genes required for mitosis, and therefore, is expressed in all proliferating cells. Interestingly, the FoxM1 gene is over-expressed in almost all epithelial cell-derived cancers. Moreover, its over-expression in breast cancer is considered to be a biomarker for poor prognosis. Recently, we showed that the activity of FoxM1 is critical for reducing the levels of reactive oxygen species (ROS) in dividing normal and tumor cells. Tumor cells expressing a ROS-inducing oncogene (such as Akt or Ras) are addicted to FoxM1 for their survival, indicating that FoxM1 is a molecular target for cancer therapy.
Previously, we showed that FoxM1 expression is essential for hepatocellular carcinoma (HCC) development. Recently, we investigated the effects of FoxM1 over-expression in the absence of its inhibitor, the tumor suppressor ARF. Transgenic expression of FoxM1 in an ARF-null background drives metastasis of HCC. We identified novel mechanisms of FoxM1 that are critical for metastasis, including epithelial-mesenchymal transition, tumor cell motility and formation of a pre-metastatic niche. Furthermore, we show that an ARF-derived peptide, which inhibits FoxM1, impedes metastasis. These observations indicate that FoxM1 is a master regulator of metastasis and that its inhibition by the tumor suppressor ARF is a critical regulatory mechanism for tumor metastasis.
DDB2 in DNA damage response: DNA damage-induced apoptosis and premature senescence are critical mechanisms of tumor suppression, as they prevent accumulation of cells with oncogenic mutations. We observed that the repair protein DDB2 plays important roles in these processes. DNA damage activates the pro-apoptotic pathways of p53. However, the p53 induced protein p21 is a dominant inhibitor of apoptosis. In the absence of DDB2, cells accumulate p21 to a high level following DNA damage and are unable to undergo apoptosis. We showed DDB2 plays an important role in the proteolysis of p21 in cells harboring un-repaired DNA damage to channel the cells to the apoptotic pathway.
DDB2 possesses gene regulatory activity. It inhibits expression of the antioxidant genes MnSOD and Catalase, which are critical for premature senescence following DNA damage, oncogenic activation and oxidative stress. Also, expression of DDB2 is increased by ROS. Thus, DDB2 functions in a feed back loop to cause persistent accumulation of ROS by inhibiting expression of the antioxidant genes. We are investigating the mechanism by which DDB2 represses MnSOD and Catalase. Our model is that DDB2 increases H3K9-tri-methylation in the promoter region of these genes.
Mouse models in the lab: DDB2-/-, Cul4A-/-, p21-/-, FoxM1fl/fl, FoxM1fl/fl MxCre, FoxM1fl/fl-ErT2-Cre: Liver cancer models: Alb-HRas and DEN/PB chemical carcinogenesis; Breast cancer models: MMTV-Neu and PyMT.
Stoyanova T, Roy, N, Bhattacharjee, S, Kopanja, D, Valli, T, Bagchi, S and Raychaudhuri, P (2012) p21 cooperates with DDB2 protein in suppression of ultraviolet-ray-induced skin cancer. J. Biol. Chem. 287: 3019-3028.
Carr JR, Kiefer MM, Park HJ, Li J, Wang Z, Fontarosa J, DeWaal D, Kopanja D, Benevolenskaya EV, Guzman G, Raychaudhuri P (2012) FoxM1 regulates mammary luminal cell fate. Cell Reports 1: 715-729.
Wang Z, Zheng Y, Park HJ, Li J, Carr JR, Kiefer MM, Kopanja D, Bagchi S and Raychaudhuri P (2013) Targeting FoxM1 effectively retards p53-null lymphoma and Sarcoma. Mol. Cancer Ther. (In press).
Roy N, Bommi PV, Bhat UG, Bhattacharjee S, Elangovan I, Li J, Patra KC, Kopanja D, Blunier A, Benya R, Bagchi S and Raychaudhuri P (2013) DDB2 suppresses epithelial to mesenchymal transition in colon cancer. Cancer Res. (In press).