Exposure to environmental agents, such as ultraviolet (UV) irradiation, chemical carcinogens, and chemotherapeutic agents, causes DNA damage that results in malignant transformation and carcinogenesis. The p53 tumor suppressor plays a critical role in cellular responses to DNA damage by suppressing cell transformation and by maintaining the genetic integrity of the cell. The suppression and maintenance are achieved through accumulation of the p53 protein after DNA damage and through p53-induced transcriptional activation of a number of gene products, such as p21 and PUMA, to mediate either cell cycle arrest or apoptosis. Since elevated levels of the p53 protein are believed to be important in initiating the events leading to cell cycle arrest or apoptosis after DNA damage, the mechanism of p53 accumulation after DNA damage has been a major area of cancer research for the past two decades. Although it is widely accepted that the accumulation of p53 is regulated by protein stabilization through its interaction with MDM2 protein, there is clear evidence indicating that increased synthesis of p53 in response to DNA damage also contributes to the induction of p53. However, the mechanisms underlying the regulation of p53 translation in response to DNA damage are still poorly understood. We have made a novel discovery that an internal ribosome entry site (IRES) sequence is present in the 5'-untranslated region (UTR) of the p53 mRNA. IRES sequences allow cap-independent protein translation under cyto- or genotoxic conditions. We hypothesize that this IRES sequence plays a key role in regulating p53 synthesis in response to DNA damage. Our recent results have also provide initial evidence that defective p53 synthesis after DNA damage may lead to malignant transformation of tumor cells that express wild-type p53. The long term goal of this project is to further study the mechanism(s) underlying the translational regulation of p53 by the IRES in response to various DNA damage signals, such as chemotherapeutic agents and UV irradiation, and to determine whether alteration in p53 IRES activity could result in tumorigenic transformation in cancer cells. The findings from this proposal may lead to a better understanding of p53 synthesis following DNA damage and provide new insight into the functional link between p53 tumor suppressor inactivation and the pathogenesis of cancer.
In this project, we will analyze translational regulation of the p53 tumor suppressor in response to DNA damage caused by environmental cues and chemotherapeutic agents. Moreover, we will also examine the relationship between defective p53 synthesis after DNA damage and the tumorigenic transformation of cancer cells. The findings from this project may lead to a better understanding of p53 synthesis following DNA damage and provide new insight into the mechanisms of p53 tumor suppressor inactivation in the pathogenesis of cancer.
|Halaby, Marie-Jo; Li, Yan; Harris, Benjamin R et al. (2015) Translational Control Protein 80 Stimulates IRES-Mediated Translation of p53 mRNA in Response to DNA Damage. Biomed Res Int 2015:708158|
|Halaby, Marie-Jo; Harris, Benjamin R E; Miskimins, W Keith et al. (2015) Deregulation of Internal Ribosome Entry Site-Mediated p53 Translation in Cancer Cells with Defective p53 Response to DNA Damage. Mol Cell Biol 35:4006-17|