p53 amyloid formation leading to its loss of function: implications in cancer pathogenesis.

Autor: Ghosh S; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India., Salot S; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India., Sengupta S; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India., Navalkar A; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India., Ghosh D; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India., Jacob R; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India., Das S; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India.; IITB-Monash Research Academy, Indian Institute of Technology Bombay, Mumbai, India., Kumar R; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India., Jha NN; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India., Sahay S; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India., Mehra S; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India., Mohite GM; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India., Ghosh SK; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India., Kombrabail M; Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai, India., Krishnamoorthy G; Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, India.; Department of Biotechnology, Anna University, Chennai, India., Chaudhari P; Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Navi Mumbai, India., Maji SK; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2017 Oct; Vol. 24 (10), pp. 1784-1798. Date of Electronic Publication: 2017 Jun 23.
DOI: 10.1038/cdd.2017.105
Abstrakt: The transcriptional regulator p53 has an essential role in tumor suppression. Almost 50% of human cancers are associated with the loss of p53 functions, where p53 often accumulates in the nucleus as well as in cytoplasm. Although it has been previously suggested that amyloid formation could be a cause of p53 loss-of-function in subset of tumors, the characterization of these amyloids and its structure-function relationship is not yet established. In the current study, we provide several evidences for the presence of p53 amyloid formation (in human and animal cancer tissues); along with its isolation from human cancer tissues and the biophysical characterization of these tissue-derived fibrils. Using amyloid seed of p53 fragment (P8, p53(250-257)), we show that p53 amyloid formation in cells not only leads to its functional inactivation but also transforms it into an oncoprotein. The in vitro studies further show that cancer-associated mutation destabilizes the fold of p53 core domain and also accelerates the aggregation and amyloid formation by this protein. Furthermore, we also show evidence of prion-like cell-to-cell transmission of different p53 amyloid species including full-length p53, which is induced by internalized P8 fibrils. The present study suggests that p53 amyloid formation could be one of the possible cause of p53 loss of function and therefore, inhibiting p53 amyloidogenesis could restore p53 tumor suppressor functions.
Databáze: MEDLINE
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