title: Dual role of p53 amyloid formation in cancer; loss of function and gain of toxicity.
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.
authors.affiliation: George and Cynthia Woods Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-1045, USA.
authors.forename: Cristian A
authors.initials: CA
authors.lastname: Lasagna-Reeves
authors.forename: Audra L
authors.initials: AL
authors.lastname: Clos
authors.forename: Diana
authors.initials: D
authors.lastname: Castillo-Carranza
authors.forename: Urmi
authors.initials: U
authors.lastname: Sengupta
authors.forename: Marcos
authors.initials: M
authors.lastname: Guerrero-Muñoz
authors.forename: Brent
authors.initials: B
authors.lastname: Kelly
authors.forename: Richard
authors.initials: R
authors.lastname: Wagner
authors.forename: Rakez
authors.initials: R
authors.lastname: Kayed
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis; D002280:Basal Cell Carcinoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D011487:Protein Conformation; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016159:Tumor Suppressor Protein p53; D004247:DNA