Oncogenic Gain of Function in Glioblastoma Is Linked to Mutant p53 Amyloid Oligomers

Murilo M Pedrote; Michelle F Motta; Giulia D S Ferretti; Douglas R Norberto; Tania C L S Spohr; Flavia R S Lima; Enrico Gratton; Jerson L Silva; Guilherme A P de Oliveira

doi:10.1016/j.isci.2020.100820

Oncogenic Gain of Function in Glioblastoma Is Linked to Mutant p53 Amyloid Oligomers

iScience. 2020 Feb 21;23(2):100820. doi: 10.1016/j.isci.2020.100820. Epub 2020 Jan 8.

Authors

Murilo M Pedrote¹, Michelle F Motta¹, Giulia D S Ferretti¹, Douglas R Norberto², Tania C L S Spohr³, Flavia R S Lima⁴, Enrico Gratton⁵, Jerson L Silva⁶, Guilherme A P de Oliveira⁷

Affiliations

¹ Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Science and Technology for Structural Biology and Bioimaging, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro 21941-901, Brazil.
² Universidade Federal do ABC, Centro de Ciências Naturais e Humanas. Av. dos Estados, 5001 Sta. Terezinha, Santo André, São Paulo 21941-590, Brazil.
³ Laboratório de Biomedicina do Cérebro, Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Secretaria de Estado de Saúde, Rio de Janeiro, Brazil.
⁴ Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
⁵ Laboratory for Fluorescence Dynamics, Biomedical Engineering Department, University of California, Irvine, CA 92697-2717, USA.
⁶ Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Science and Technology for Structural Biology and Bioimaging, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro 21941-901, Brazil. Electronic address: jerson@bioqmed.ufrj.br.
⁷ Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Science and Technology for Structural Biology and Bioimaging, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro 21941-901, Brazil; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908-0733, USA. Electronic address: gaugusto@bioqmed.ufrj.br.

Abstract

Tumor-associated p53 mutations endow cells with malignant phenotypes, including chemoresistance. Amyloid-like oligomers of mutant p53 transform this tumor suppressor into an oncogene. However, the composition and distribution of mutant p53 oligomers are unknown and the mechanism involved in the conversion is sparse. Here, we report accumulation of a p53 mutant within amyloid-like p53 oligomers in glioblastoma-derived cells presenting a chemoresistant gain-of-function phenotype. Statistical analysis from fluorescence fluctuation spectroscopy, pressure-induced measurements, and thioflavin T kinetics demonstrates the distribution of oligomers larger than the active tetrameric form of p53 in the nuclei of living cells and the destabilization of native-drifted p53 species that become amyloid. Collectively, these results provide insights into the role of amyloid-like mutant p53 oligomers in the chemoresistance phenotype of malignant and invasive brain tumors and shed light on therapeutic options to avert cancer.

Keywords: Biophysics; Cancer; Protein Structure Aspects; Structural Biology.