Hdmx and Mdm2 can repress transcription activation by p53 but not by p63

Little, Natalie A.; Jochemsen, Aart G.

doi:10.1038/sj.onc.1204615

Cited by 57 publications

(61 citation statements)

References 36 publications

(26 reference statements)

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“…Recently, elevated expression of MDM4 was demonstrated to be a key determinant of impaired p53 func tion in melanoma (Gembarska et al, 2012). Although previous in vitro data indicate that both MDM2 and MDM4 could not repress transactivation of p63 isoforms (Little and Jochemsen, 2001), our results suggest otherwise in melanoma. Our data propose a role for p63 in modulating expression of p53, MDM2, and MDM4 through depletion of MDM2 (possibly through degradation) and MDM4, thus increasing p53mediated che mosensitivity in melanoma.…”

Section: Depletion Of P63 Sensitizes Melanoma Cells To a Mitochondriacontrasting

confidence: 55%

p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis

Matin¹,

Chikh²,

Chong³

et al. 2013

J Cell Biol

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Section: Depletion Of P63 Sensitizes Melanoma Cells To a Mitochondriacontrasting

confidence: 55%

p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis

Matin¹,

Chikh²,

Chong³

et al. 2013

J Cell Biol

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“…Therefore, the conformational change induced by arginine at position 268 may prevent conformational changes required for HDM2 docking and thus inhibit HDM2-mediated ubiqitination of p53. Interestingly, HDM2 binds to p63 and p73 at their amino termini but fails to ubiquitinate these proteins (51,52). It is possible that the DBDs of p63 and p73, with the arginine at 268, are not conformationally flexible to allow HDM2 docking and subsequent ubiquitination.…”

Section: Discussionmentioning

confidence: 99%

SCH529074, a Small Molecule Activator of Mutant p53, Which Binds p53 DNA Binding Domain (DBD), Restores Growth-suppressive Function to Mutant p53 and Interrupts HDM2-mediated Ubiquitination of Wild Type p53

Demma¹,

Maxwell²,

Ramos³

et al. 2010

Journal of Biological Chemistry

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Abrogation of p53 function occurs in almost all human cancers, with more than 50% of cancers harboring inactivating mutations in p53 itself. Mutation of p53 is indicative of highly aggressive cancers and poor prognosis. The vast majority of mutations in p53 occur in its core DNA binding domain (DBD) and result in inactivation of p53 by reducing its thermodynamic stability at physiological temperature. Here, we report a small molecule, SCH529074, that binds specifically to the p53 DBD in a saturable manner with an affinity of 1-2 M. Binding restores wild type function to many oncogenic mutant forms of p53. This small molecule reactivates mutant p53 by acting as a chaperone, in a manner similar to that previously reported for the peptide CDB3. Binding of SCH529074 to the p53 DBD is specifically displaced by an oligonucleotide with a sequence derived from the p53-response element. In addition to reactivating mutant p53, SCH529074 binding inhibits ubiquitination of p53 by HDM2. We have also developed a novel variant of p53 by changing a single amino acid in the core domain of p53 (N268R), which abolishes binding of SCH529074. This amino acid change also inhibits HDM2-mediated ubiquitination of p53. Our novel findings indicate that through its interaction with p53 DBD, SCH529074 restores DNA binding activity to mutant p53 and inhibits HDM2-mediated ubiquitination.

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“…A short isoform of p21 ras, p19 ras, was found to suppress ras-induced transformation by abrogating the p73-MDM2 interaction, leading to p73 activation (Jeong et al, 2006). Whether MDM2 associates significantly with p63 or plays a role in regulating p63 stability and activity remains inconclusive (Little and Jochemsen, 2001;Calabro et al, 2002). Additional E3 ubiquitin ligases have been found to interact with p73 and p63.…”

Section: Regulation Of P63 and P73 Activitymentioning

confidence: 99%

p63 and p73 in human cancer: defining the network

2007

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The p53-related genes p63 and p73 exhibit significant structural homology to p53; however, they do not function as classical tumor suppressors and are rarely mutated in human cancers. Both p63 and p73 exhibit tissue-specific roles in normal development and a complex contribution to tumorigenesis that is due to their expression as multiple protein isoforms. The predominant p63/p73 isoforms expressed both in normal development and in many tumors lack the conserved transactivation (TA) domain; these isoforms instead exhibit a truncated N-terminus (DN) and function at least in part as transcriptional repressors. p63 and p73 isoforms are regulated through both transcriptional and post-translational mechanisms, and they in turn regulate diverse cellular functions including proliferation, survival and differentiation. The net effect of p63/p73 expression in a given context depends on the ratio of TA/DN isoforms expressed, on physical interaction between p63 and p73 isoforms, and on functional interactions with p53 at the promoters of specific downstream target genes. These multifaceted interactions occur in diverse ways in tumor-specific contexts, demonstrating a functional 'p53 family network' in human tumorigenesis. Understanding the regulation and mechanistic contributions of p63 and p73 in human cancers may ultimately provide new therapeutic opportunities for a variety of these diseases.

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Hdmx and Mdm2 can repress transcription activation by p53 but not by p63

Cited by 57 publications

References 36 publications

p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis

p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis

SCH529074, a Small Molecule Activator of Mutant p53, Which Binds p53 DNA Binding Domain (DBD), Restores Growth-suppressive Function to Mutant p53 and Interrupts HDM2-mediated Ubiquitination of Wild Type p53

p63 and p73 in human cancer: defining the network

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