MDM2 and MDMX can interact differently with ARF and members of the p53 family

Wang, Xiaoqi; Arooz, Talha; Siu, Wai Yi; Chiu, Clarissa H.S.; Lau, Anita Wan Sze; Yamashita, Katsumi; Poon, Randy Y. C.

doi:10.1016/s0014-5793(01)02124-x

Cited by 82 publications

(75 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The results presented here are supported by two recent reports that appeared after submission of this manuscript (Kojima et al, 2001;Wang et al, 2001).…”

supporting

confidence: 91%

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

Little

Jochemsen

2001

Oncogene

View full text Add to dashboard Cite

“…The results presented here are supported by two recent reports that appeared after submission of this manuscript (Kojima et al, 2001;Wang et al, 2001).…”

supporting

confidence: 91%

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

Little

Jochemsen

2001

Oncogene

View full text Add to dashboard Cite

“…Thus, it is plausible that Nutlin-3 could also disrupt the p73-HDMX complex. Although a physical interaction between exogenous p73 and HDMX has been described (Ongkeko et al, 1999;Wang et al, 2001), further studies will be required to determine whether p73 and HDMX form endogenous complexes in cancer cells and whether Nutlin-3 can disrupt this complex.…”

Section: Discussionmentioning

confidence: 99%

HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function

et al. 2007

View full text Add to dashboard Cite

Nutlin-3, a small molecule inhibitor, activates p53 by disrupting p53-HDM2 association. In this study, we found that Nutlin-3 suppressed cell growth and induced apoptosis in the absence of wild-type p53, suggesting a p53-independent mechanism for Nutlin-3-induced cell death. Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death. Since HDM2, a key negative regulator of p53, also binds to and inhibits p73, we asked whether p73 could mediate Nutlin-3-induced apoptosis. We demonstrate that Nutlin-3 inhibits endogenous binding between the proapoptotic p73 isoform TAp73a and HDM2 in p53-null cells. Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. p73 knockdown by siRNA results in rescue of Nutlin-3-treated cells, indicating that Nutlin-3-induced apoptosis is, at least in part, p73 dependent. In addition, Nutlin-3 treatment increases TAp73a protein levels with prolongation of p73 half-life. These results provide the first evidence that Nutlin-3 disrupts endogenous p73-HDM2 interaction and enhances the stability and proapoptotic activities of p73 and thus, provides a rationale for the use of Nutlin-3 in the large number of human tumors in which p53 is inactivated.

show abstract

“…46,47 Less is known about the physical association of MDM2 and MDMX with p63. Some researchers found lack of interaction for both MDM2 and MDMX, 48,49 whereas others were able to detect MDM2-p63 complexes, although reporting contradictory effects on p63 function. 42,50 The crucial amino acids required for MDM2 binding are conserved in p63, but molecular modeling suggests that other residues in the N-terminal domain of p63 may render this interaction significantly weaker.…”

Section: Mdm2mentioning

confidence: 99%

p53-family proteins and their regulators: hubs and spokes in tumor suppression

2010

View full text Add to dashboard Cite

The tumor suppressor p53 is a central hub in a molecular network controlling cell proliferation and death in response to potentially oncogenic conditions, and a wide array of covalent modifications and protein interactions modulate the nuclear and cytoplasmic activities of p53. The p53 relatives, p73 and p63, are entangled in the same regulatory network, being subject at least in part to the same modifications and interactions that convey signals on p53, and actively contributing to the resulting cellular output. The emerging picture is that of an interconnected pathway, in which all p53-family proteins are involved in the response to oncogenic stress and physiological inputs. Therefore, common and specific interactors of p53-family proteins can have a wide effect on function and dysfunction of this pathway. Many years of research have uncovered an impressive number of p53-interacting proteins, but much less is known about protein interactions of p63 and p73. Yet, many interactors may be shared by multiple p53-family proteins, with similar or different effects. In this study we review shared interactors of p53-family proteins with the aim to encourage research into this field; this knowledge promises to unveil regulatory elements that could be targeted by a new generation of molecules, and allow more efficient use of currently available drugs for cancer treatment.

show abstract

MDM2 and MDMX can interact differently with ARF and members of the p53 family

Cited by 82 publications

References 58 publications

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

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

HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function

p53-family proteins and their regulators: hubs and spokes in tumor suppression

Contact Info

Product

Resources

About