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Oncogenic gain of function due to p53 amyloids occurs through aberrant alteration of cell cycle and proliferation
Journal
Journal of Cell Science
ISSN
00219533
Date Issued
2022-01-01
Author(s)
Navalkar, Ambuja
Paul, Ajoy
Sakunthala, Arunima
Pandey, Satyaprakash
Dey, Amit Kumar
Saha, Sandhini
Sahoo, Sarthak
Jolly, Mohit Kumar
Maiti, Tushar K.
Maji, Samir K.
Abstract
Transcription factor p53 (also known as TP53) has been shown to aggregate into cytoplasmic and nuclear inclusions, compromising its native tumor suppressive functions. Recently, p53 has been shown to form amyloids, which play a role in conferring cancerous properties to cells, leading to tumorigenesis. However, the exact pathways involved in p53 amyloid-mediated cellular transformations are unknown. Here, using an in cellulo model of full-length p53 amyloid formation, we demonstrate the mechanism of loss of p53 tumorsuppressive function with concomitant oncogenic gain of functions. Global gene expression profiling of cells suggests that p53 amyloid formation dysregulates genes associated with the cell cycle, proliferation, apoptosis and senescence along with major signaling pathways. This is further supported by a proteome analysis, showing a significant alteration in levels of p53 target proteins and enhanced metabolism, which enables the survival of cells. Our data indicate that specifically targeting the key molecules in pathways affected by p53 amyloid formation, such as cyclin-dependent kinase-1, leads to loss of the oncogenic phenotype and induces apoptosis of cells. Overall, our work establishes the mechanism of the transformation of cells due to p53 amyloids leading to cancer pathogenesis.
Volume
135
Subjects