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ABSTRACT
Loss of p53 function is largely responsible for the occurrence of cancer in humans. Aggregation of mutant p53 has been found in multiple cancer cell types, suggesting a role of aggregation in loss of p53 function and cancer development. The p53 protein has recently been hypothesized to possess a prion-like conformation, although experimental evidence is lacking. Here, we report that human p53 can be inactivated upon exposure to preformed fibrils containing an aggregation-prone sequence-specific peptide, PILTIITL, derived from p53, and the inactive state was found to be stable for many generations. Importantly, we provide evidence of a prion-like transmission of these p53 aggregates. This study has significant implications for understanding cancer progression due to p53 malfunctioning without any loss-of-function mutation or occurrence of transcriptional inactivation. Our data might unlock new possibilities for understanding the disease and will lead to rational design of p53 aggregation inhibitors for the development of drugs against cancer.
ACKNOWLEDGMENTS
S.S. is supported by IIT institutional funding. S.K.M. acknowledges IIT Bombay health care seed funding, a Lady Tata memorial trust young researcher fellowship, and the Department of Science and Technology (grant number EMR/2014/001233) for funding. S.K.G. is supported by DST and DBT Government of India (grant no. SB/SO/BB/125/2013 and BT/PR13962/BRB/10/798/2010).
We acknowledge P. J. Bhat, Deepak Sharma, and R. D. Iggo for providing reagents. We acknowledge Charles Glabe, UC Urvine, for the kind gift of OC antibody. We also thank Shimul Salot, Saikat Ghosh, Ankita Chavan, and Priyanka Mittal for their help in the experiments.