4909

Eukaryotic cells have evolved complex molecular mechanisms through which they sense and process aberrant proteins. The task of determining the fate of structurally unsound products is accomplished by an intricate network of molecules, which includes molecular chaperones, co-chaperones, several classes of ubiquitin conjugating enzymes and the proteasome. However, with molecular mechanisms not completely clear, some misfolded proteins elude degradation leading to detrimental effects ranging from neurodegenerative disorders to cancer. One of the best examples in this respect is represented by the p53 gene product, which in its mutant, tumor-associated version, escapes ubiquitin-mediated proteolysis. We have identified a novel domain of the acetyltransferase p300 that has similarity with a prion-like domain of a family of C. elegans genes, Abu. Mechanistically, we demonstrate that this domain of p300 is involved in recognition of structurally abnormal mutant forms of p53 and of other misfolded ubiquitinated proteins. p300 regulates the interaction of misfolded mutant forms of p53 with the chaperone machinery, and is an important determinant of the stability of these proteins. Intriguingly, we demonstrate that these effects are at least in part mediated by p300-mediated control of a cytoplasmic organelle that normally acts as a storage and processing device for misfolded proteins, the aggresome. Both p300 and mutant p53 localize in aggresomes and elimination of p300 via a specific siRNA reduces aggresome formation and leads to degradation of p53. Similar effects are achieved with the knock-down of the deacetylase HDAC6, a protein with almost exclusive activities on aggresome formation. Finally, like Abu genes promote survival in metazoans faced with a surplus of incorrectly folded proteins, similarly, p300 protects from apoptosis in mammalian cells overwhelmed with misfolded proteins. These data suggest that p300 acts as a general determinant of sensitivity of cells to misfolded proteins, and suggest a general model for its mode of operations in protein-triage decisions in pathological conditions.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA