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• W2027898769 abstract "In this issue, Trinidad et al., 2013Trinidad A.G. Muller P.A.J. Cuellar J. Klejnot M. Nobis M. Valpuesta J.M. Vousden K.H. Mol. Cell. 2013; 50 (this issue): 805-817Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar show that CCT/TRiC is a chaperone required for p53 folding, thus providing another layer of regulation of p53 function, with implications for cancer therapeutics targeting the p53 pathway. In this issue, Trinidad et al., 2013Trinidad A.G. Muller P.A.J. Cuellar J. Klejnot M. Nobis M. Valpuesta J.M. Vousden K.H. Mol. Cell. 2013; 50 (this issue): 805-817Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar show that CCT/TRiC is a chaperone required for p53 folding, thus providing another layer of regulation of p53 function, with implications for cancer therapeutics targeting the p53 pathway. Loss of p53 function in human cancer most frequently occurs via single amino acid missense mutations (Edlund et al., 2012Edlund K. Larsson O. Ameur A. Bunikis I. Gyllensten U. Leroy B. Sundström M. Micke P. Botling J. Soussi T. Proc. Natl. Acad. Sci. USA. 2012; 109: 9551-9556Crossref PubMed Scopus (71) Google Scholar). Missense mutations that destroy the normal function of p53 are only part of the story, however; many of these p53 mutants do not only lose normal function but also gain functions that enhance tumor progression (Halevy et al., 1990Halevy O. Michalovitz D. Oren M. Science. 1990; 250: 113-116Crossref PubMed Scopus (205) Google Scholar). Among the new functions acquired by mutant p53, the best-characterized is the ability to drive the invasive growth of tumor cells (Muller et al., 2009Muller P.A. Caswell P.T. Doyle B. Iwanicki M.P. Tan E.H. Karim S. Lukashchuk N. Gillespie D.A. Ludwig R.L. Gosselin P. et al.Cell. 2009; 139: 1327-1341Abstract Full Text Full Text PDF PubMed Scopus (616) Google Scholar). It is in this chapter of the story that the results of Trinidad et al., 2013Trinidad A.G. Muller P.A.J. Cuellar J. Klejnot M. Nobis M. Valpuesta J.M. Vousden K.H. Mol. Cell. 2013; 50 (this issue): 805-817Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar; in this issue of Molecular Cell) provide an unexpected twist. They show that the ability to enhance invasive growth is not strictly a property of mutant forms of p53 but is conferred even by the wild-type p53 protein if its proper folding is blocked. Specifically, in a search for new partners that might selectively bind mutant p53 and explain its gain-of-function activities, Trinidad et al., 2013Trinidad A.G. Muller P.A.J. Cuellar J. Klejnot M. Nobis M. Valpuesta J.M. Vousden K.H. Mol. Cell. 2013; 50 (this issue): 805-817Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar made the somewhat remarkable discovery that seven of the eight proteins that comprise the CCT chaperone complex interact with both mutant and wild-type p53. CCT (or TRiC) is an evolutionarily conserved, 16 subunit complex that contains two copies of each of the eight individual proteins (i.e., a dimer of identical octamers) (Yébenes et al., 2011Yébenes H. Mesa P. Muñoz I.G. Montoya G. Valpuesta J.M. Trends Biochem. Sci. 2011; 36: 424-432Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). The central function of CCT is to mechanically enforce the correct folding of its client proteins, via a process that requires ATP hydrolysis. So what role might this professional protein-folding complex be playing in controlling the structure of p53? And why is it interacting with both the wild-type protein and a mutant whose structure is so corrupted that it no longer functions to suppress cancer? To help us understand the issues, we have two decades of increasingly elegant structural studies of p53 to guide us (reviewed in Okorokov and Orlova, 2009Okorokov A.L. Orlova E.V. Curr. Opin. Struct. Biol. 2009; 19: 197-202Crossref PubMed Scopus (48) Google Scholar). p53 is an obligate and intricate homotetramer that also interacts in a nucleotide sequence-specific manner with its palindromic binding sites in the genome. One of the major classes of p53 mutations in human cancer inactivates the protein by altering the conformation of the tetramer; a second blocks its interaction with the DNA binding site, without inducing overt structural defects. Understanding chaperones like CCT that regulate the folding of p53 has important clinical implications. Clever strategies have begun to emerge that use small molecules or peptides (e.g., PRIMA-1met) to correct misfolded mutant p53 protein in tumor cells, thus allowing the protein to regain some of the biochemical activities that are required for tumor suppression (Issaeva et al., 2003Issaeva N. Friedler A. Bozko P. Wiman K.G. Fersht A.R. Selivanova G. Proc. Natl. Acad. Sci. USA. 2003; 100: 13303-13307Crossref PubMed Scopus (130) Google Scholar). In addition to genetic lesions in p53 itself, human cancer cells have discovered other creative ways to inactivate this critical tumor suppressor, including overexpression of p53 inhibitors like MDM2 and loss of p53 activators like p14ARF/CDKN2A (Levine and Oren, 2009Levine A.J. Oren M. Nat. Rev. Cancer. 2009; 9: 749-758Crossref PubMed Scopus (1345) Google Scholar). The discoveries of Trinidad et al., 2013Trinidad A.G. Muller P.A.J. Cuellar J. Klejnot M. Nobis M. Valpuesta J.M. Vousden K.H. Mol. Cell. 2013; 50 (this issue): 805-817Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar suggest that inactivation of CCT function could be a very efficient mechanism by which a tumor cell might deactivate the tumor-suppressor function of p53 and simultaneously enhance its gain-of-function activities that are protumorigenic. Is there any evidence for this? In fact there is modest yet rapidly accumulating evidence that CCT is altered in cancer, and public repositories like COSMIC show mutations in several of the CCT subunits (Forbes et al., 2011Forbes S.A. Bindal N. Bamford S. Cole C. Kok C.Y. Beare D. Jia M. Shepherd R. Leung K. Menzies A. et al.Nucleic Acids Res. 2011; 39: D945-D950Crossref PubMed Scopus (1814) Google Scholar). Whether these mutations activate or inactivate CCT (or are inert) remains to be determined, but this newly discovered link to p53 will certainly focus a great deal of attention on the CCT/cancer connection. Interestingly, recent evidence shows that many of the CCT subunits are overexpressed cancer. Here again, whether this leads to enhanced function or decreased function, perhaps due to suboptimal stoichiometry within the CCT complex, remains unknown. However, preliminary experimental evidence supports the model that overexpression of individual CCT complex subunits in human cancer correlates with decreased CCT activity (Boudiaf-Benmammar et al., 2013Boudiaf-Benmammar C. Cresteil T. Melki R. PLoS ONE. 2013; 8: e60895https://doi.org/10.1371/journal.pone.0060895Crossref PubMed Scopus (53) Google Scholar), and by extension misfolded wild-type p53. Alternatively, it is also possible that CCT differs from p53 regulators that are altered in cancer (such as MDM2 and p14ARF/CDKN2A), because it has other essential clients whose misfolding is not compatible with the survival of cancer cells. As hinted at above, the discovery of a pathway that limits protumorigenic properties of wild-type p53 has important therapeutic implications. Drugs like Nutlin-3, which enhance the function of wild-type p53 by inhibiting negative regulation by MDM2, have entered clinical trials (Saha et al., 2013Saha M.N. Qiu L. Chang H. J. Hematol. Oncol. 2013; 6: 23Crossref PubMed Scopus (89) Google Scholar). The central criterion for the success of this class of compounds is that p53 be in a wild-type state in the patient’s tumor cells. The findings reported by Trinidad et al., 2013Trinidad A.G. Muller P.A.J. Cuellar J. Klejnot M. Nobis M. Valpuesta J.M. Vousden K.H. Mol. Cell. 2013; 50 (this issue): 805-817Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar raise the cautionary flag that it may not be advantageous to enhance wild-type p53 function in some settings (e.g., in cells that have accumulated defects in the CCT pathway). Taking this one step further, perhaps the protumorigenic effects of wild-type p53 in CCT-deficient cells could be blocked by treatment with compounds like PRIMA-1met, which were designed to help restore tumor suppressor function to mutant versions of p53 where conformation has been corrupted by point mutations. While these potential implications for cancer therapy are exciting, there are still a number of confusing details about the CCT/p53 pathway that need to be worked out. The mutation of R175 to H and the depletion of CCT from cells carrying wild-type p53 both result in a misfolded protein, and both result in enhanced invasive growth. However, the causal link between misfolding and invasive growth is undercut by the fact that mutation of R273 to H also creates a protein which enhances invasive growth but does result in overt misfolding of p53. (The R273H mutant eliminates the normal functions of p53 by blocking its ability to interact with DNA, since R273 is a site of direct contact with the p53 response elements in the genome.) Thus the mechanism by which CCT blocks the promotion of invasive growth by wild-type p53 is likely more complex than a direct chaperone activity. Ultimately, the long-term excitement about this newly discovered mechanism for controlling p53 will be determined by the strength of the genetic proof for its importance in animal models and in human cancer. Interaction of p53 with the CCT Complex Promotes Protein Folding and Wild-Type p53 ActivityTrinidad et al.Molecular CellJune 6, 2013In Briefp53 is a transcription factor that mediates tumor suppressor responses. Correct folding of the p53 protein is essential for these activities, and point mutations that induce conformational instability of p53 are frequently found in cancers. These mutant p53s not only lose wild-type activity but can also acquire the ability to promote invasion and metastasis. We show that folding of wild-type p53 is promoted by an interaction with the chaperonin CCT. Depletion of this chaperone in cells results in the accumulation of misfolded p53, leading to a reduction in p53-dependent gene expression. Full-Text PDF Open Access" @default.
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• W2027898769 title "p53: The TRiC Is Knowing When to Fold ‘Em" @default.
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