The long-term goal of our research is to understand the chemical, molecular and cellular mechanisms that govern cell proliferation, differentiation, and apoptosis and often occur as the early events of carcinogenesis, involving the MDM2-p53 feedback loop. Research supported by my previously funded R01 and by many other groups has now firmly established the role of ribosomal proteins (RP), such as RPL11, RPL5, and RPL23, in p53 response to various cellular and environmental carcinogens or chemicals, including endogenous and exogenous compounds, which may cause ribosomal stress, by directly binding to MDM2 and inhibiting its E3 ubiquitin ligase activity toward p53. Also more MDM2-binding RPs including RPL26, RPS7, RPS3 and RPS14 have been identified to play a role in this pathway. It is now acknowledged that this ribosomal stress-p53 pathway plays a vital role in cell growth, apoptosis, and tumorigenesis, and is also highly pertinent to cancers and cancer-prone genetic diseases, such as 5q-syndrome and Diamond-Blackfan anemia (DBA). Although a tremendous progress has been made in understanding the biological importance of this pathway in p53 response and tumorigenesis, additional, remarkably important and challenging questions still remain to be addressed. For example, it still remains puzzling how mechanistically these RPs function to inactivate MDM2. Also it is particularly intriguing why so many RPs are needed to suppress MDM2 and to activate p53 in response to ribosomal stress-causing chemical, carcinogens and intracellular abnormalities. Finally, would these MDM2-binding ribosomal proteins play a role in p53 activation as pathogenesis of 5q-syndrome or DBA? Thus, we will continue our in-depth interrogation into this signaling pathway in this renewal application. In light of available information including our preliminary studies, I propose that the aforementioned MDM2- binding RPs may work as a dynamic sub-ribosomal complex, instead of individually, to suppress MDM2 activity in a well choreographic way assembled at the central acidic and Zinc Finger domains of this E3 ubiquitin ligase in response to RS caused by various agents or genetic alterations including metabolic disorder or genetic diseases, leading to p53 activation.
Two specific aims are planned to test this hypothesis: 1) To illustrate structural and functional insight into the mechanisms governing the inhibition of MDM2 by RPs;2) To determine if RPs act as a ribosomal stress-induced dynamic sub-ribosomal complex to suppress MDM2 activity in cells and animals. Achieving these short term goals would allow us to better understanding how these ribosomal proteins function as a dynamic complex in cells or animals to suppress MDM2- mediated p53 ubiquitination and consequent inactivation upon exposure to endogenous and exogenous compounds that cause ribosomal stress. The outcomes from the proposed experiments would not only provide a possible mechanistic explanation for cancer- or disease-related phenotype, but also offer a framework for using the Zinc Finger domain of MDM2 as a potential target for the development of anti-cancer drugs in the future.
The most important cancer-relevant p53 tumor suppressor gene is highly regulated by a so-called oncoprotein named MDM2 via a feedback mechanism during cell growth and cell division as a cause of cancer formation, but this feedback regulation is subjected to additional level of controls by a group of newly identified ribosomal proteins including those by this laboratory in response to different cell and environmental chemical compounds that cause ribosomal stress. Hence the proposed studies in this application are designed to dig out molecular insight into how these proteins may regulate this MDM2-p53 feedback loop and completion of these studies will uncover new information that would be useful for future anti-cancer drug discovery, which will be tremendously beneficial to Public Health in the near future, as cancer is currently the number 1 cause of disease-related deaths in the USA.
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|Lo, D; Zhang, Y; Dai, M-S et al. (2015) Nucleostemin stabilizes ARF by inhibiting the ubiquitin ligase ULF. Oncogene 34:1688-97|
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