Cellular senescence and apoptosis are critical defense mechanisms that allow higher organisms, including humans, to escape oncogenic consequences. For example, expression of an oncogene (such as Ras) elevates the cellular levels of reactive oxygen species (ROS). A moderate increase in ROS leads to premature senescence, whereas a very high level leads to apoptosis. These two defense mechanisms are often disrupted during development of a tumor cell. The tumors of the hematopoietic lineage, however, often retain these functions;and they undergo apoptosis or senescence upon treatments with DNA damaging agents. In those tumors, disruption of the apoptosis or senescence programs leads to development of drug resistance. During the last funding period, we carried out detailed analyses on the mechanism by which the nucleotide excision repair protein DDB2, encoded by the XP-E gene, participates in DNA repair. Surprisingly, during those studies, we observed evidence that DDB2 plays important roles in premature senescence and DNA damage-induced apoptosis. Cells lacking DDB2 fail to undergo senescence induced by culture shock or stress and they are resistant to apoptosis induced by several genotoxic agents. In the current proposal, we plan to investigate the roles of DDB2 in the pathways of ROS-inducing oncogenes, such as Ras and Myc. We will test the hypotheses that DDB2 plays important roles in tumor development and that it is critical in sensitizing hematopoietic tumors to the DNA damaging drugs, which are used in chemotherapy.
The specific aims are: 1. How does ROS activate expression of DDB2? Does oncogene-induced accumulation of ROS require DDB2? Does DDB2 accelerate or delay oncogene-induced tumor development? 2. Does DDB2-deficiency confer resistance to chemotherapeutic drugs? Does re-expression of DDB2 sensitize resistant cells to chemotherapy? 3. How does DDB2 overcome the apoptosis-inhibitory activity of Mdm2?
Public Health Relevance: DDB2 was identified as the product of the XP-E gene, which is mutated in xeroderma pigmentosum. We found that, in addition to its role in DNA repair, DDB2 has other functions that are significant in tumor suppression. In this application, we plan to investigate the cellular pathways that are modulated by DDB2 to protect cells from becoming tumor cells. Also, we will determine potential contribution of DDB2 in sensitizing tumors to chemotherapy. Those studies will be highly relevant in designing therapy against otherwise resistant tumors.
|Roy, Nilotpal; Elangovan, Indira; Kopanja, Dragana et al. (2013) Tumor regression by phenethyl isothiocyanate involves DDB2. Cancer Biol Ther 14:108-16|
|Roy, Nilotpal; Bommi, Prashant V; Bhat, Uppoor G et al. (2013) DDB2 suppresses epithelial-to-mesenchymal transition in colon cancer. Cancer Res 73:3771-82|
|Stoyanova, Tanya; Roy, Nilotpal; Bhattacharjee, Shaumick et al. (2012) p21 cooperates with DDB2 protein in suppression of ultraviolet ray-induced skin malignancies. J Biol Chem 287:3019-28|
|Raychaudhuri, Pradip; Park, Hyun Jung (2011) FoxM1: a master regulator of tumor metastasis. Cancer Res 71:4329-33|
|Kopanja, Dragana; Roy, Nilotpal; Stoyanova, Tanya et al. (2011) Cul4A is essential for spermatogenesis and male fertility. Dev Biol 352:278-87|
|Dominguez-Brauer, Carmen; Brauer, Patrick M; Chen, Yi-Ju et al. (2010) Tumor suppression by ARF: gatekeeper and caretaker. Cell Cycle 9:86-9|
|Roy, Nilotpal; Stoyanova, Tanya; Dominguez-Brauer, Carmen et al. (2010) DDB2, an essential mediator of premature senescence. Mol Cell Biol 30:2681-92|
|Chen, Yi-Ju; Dominguez-Brauer, Carmen; Wang, Zebin et al. (2009) A conserved phosphorylation site within the forkhead domain of FoxM1B is required for its activation by cyclin-CDK1. J Biol Chem 284:30695-707|
|Stoyanova, Tanya; Roy, Nilotpal; Kopanja, Dragana et al. (2009) DDB2 decides cell fate following DNA damage. Proc Natl Acad Sci U S A 106:10690-5|
|Dominguez-Brauer, Carmen; Chen, Yi-Ju; Brauer, Patrick M et al. (2009) ARF stimulates XPC to trigger nucleotide excision repair by regulating the repressor complex of E2F4. EMBO Rep 10:1036-42|
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