Dual role of p53 amyloid formation in cancer; loss of function and gain of toxicity

Cristian A. Lasagna-Reeves, Audra L. Clos, Diana Castillo-Carranza, Urmi Sengupta, Marcos Guerrero-Muñoz, Brent Kelly, Richard Wagner, Rakez Kayed

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

The tumor suppressor p53 plays an important role in genome integrity. It is frequently mutated in all types of human cancers, making p53 a key factor in cancer progression. Two phenotypic consequences of these alterations are dominant; a loss of function and a gain of function of p53, which, in several cases, accumulates in intracellular aggregates. Although the nature of such aggregates is still unclear, recent evidence indicates that p53 can undergo conformational transitions leading to amyloid formation. Amyloid diseases, such as, Alzheimer's disease, are characterized by the accumulation of insoluble aggregates displaying the fibrillar conformation. We decided to investigate the propensity of wild type p53 to aggregate and its consequent assembly into different amyloid species, such as oligomers and fibrils; and to determine if these changes in conformation lead to a loss of function of p53. Furthermore, we analyzed cases of Basal Cell Carcinoma (BCC), for the presence of p53 amyloids. Here, we show that p53 forms amyloid oligomers and fibrils, which coincide with p53 inability of binding to DNA consensus sequences. Both p53 amyloid oligomers and fibrils were detected in BCC cancer samples. Additionally, we demonstrate that p53 oligomers are the most cytotoxic to human cell cultures.Our study reveals p53 amyloid formation and demonstrates its dual role in the pathogenesis of cancer by producing a loss of protein function and a gain of toxic function, extensively described in several amyloidogenic diseases. Our results suggest that under certain circumstances, cancer could be considered a protein-conformation disease.

Original languageEnglish (US)
Pages (from-to)963-968
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume430
Issue number3
DOIs
StatePublished - Jan 18 2013

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Amyloid
Toxicity
Oligomers
Neoplasms
Conformations
Basal Cell Carcinoma
Basal Cell Neoplasms
Protein Conformation
Poisons
DNA sequences
Consensus Sequence
Cell culture
Tumors
Alzheimer Disease
Proteins
Cell Culture Techniques
Genes
Cells
Genome

Keywords

  • Cancer: Basal Cell Carcinoma
  • Fibrils
  • Oligomers
  • P53

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

Dual role of p53 amyloid formation in cancer; loss of function and gain of toxicity. / Lasagna-Reeves, Cristian A.; Clos, Audra L.; Castillo-Carranza, Diana; Sengupta, Urmi; Guerrero-Muñoz, Marcos; Kelly, Brent; Wagner, Richard; Kayed, Rakez.

In: Biochemical and Biophysical Research Communications, Vol. 430, No. 3, 18.01.2013, p. 963-968.

Research output: Contribution to journalArticle

Lasagna-Reeves, Cristian A. ; Clos, Audra L. ; Castillo-Carranza, Diana ; Sengupta, Urmi ; Guerrero-Muñoz, Marcos ; Kelly, Brent ; Wagner, Richard ; Kayed, Rakez. / Dual role of p53 amyloid formation in cancer; loss of function and gain of toxicity. In: Biochemical and Biophysical Research Communications. 2013 ; Vol. 430, No. 3. pp. 963-968.
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