MDMX: a novel p53-binding protein with some functional properties of MDM2.

Шварц, Анна; Steegenga, Wilma T.; Riteco, N.; Laar, Theo van; Dekker, Pim; Bazuine, Merlijn; Ham, R. C. A. Van; Oordt, Willemien van der Houven van; Hateboer, G.; Eb, A. J. Van Der; Jochemsen, Aart G.

doi:10.1002/j.1460-2075.1996.tb00919.x

Cited by 566 publications

(603 citation statements)

References 54 publications

Supporting

Mentioning

584

Contrasting

Unclassified

Order By: Relevance

“…This is consistent with a predominant role of Mdm2 in normal cells of promoting p53-degradation rather than transcriptional repression by direct binding to p53 (Itahana et al, 2007). MdmX does not possess intrinsic ubiquitin E3 ligase activity towards p53 in vivo, but it binds to p53 and inhibits its transcriptional activity (Shvarts et al, 1996;Bottger et al, 1999). However, there is evidence that Mdm2-MdmX heterodimers are involved in promoting the ubiquitination of p53 (Singh et al, 2007;Uldrijan et al, 2007;Linke et al, 2008).…”

Section: Introductionsupporting

confidence: 78%

MdmX is a substrate for the deubiquitinating enzyme USP2a

et al. 2009

View full text Add to dashboard Cite

It has previously been shown that ubiquitin-specific protease 2a (USP2a) is a regulator of the Mdm2/p53 pathway. USP2a binds to Mdm2 and can deubiquitinate Mdm2 without reversing Mdm2-mediated p53 ubiquitination. Overexpression of USP2a causes accumulation of Mdm2 and promotes p53 degradation. We now show that MdmX is also a substrate for USP2a. MdmX associates with USP2a independently of Mdm2. Ectopic expression of wild-type USP2a but not a catalytic mutant prevents Mdm2-mediated degradation of MdmX. This correlates with the ability of wild-type USP2a to deubiquitinate MdmX. siRNA-mediated knockdown of USP2a in NTERA-2 testicular embryonal carcinoma cells and MCF7 breast cancer cells causes destabilization of MdmX and results in a decrease in MdmX protein levels, showing that endogenous USP2a participates in the regulation of MdmX stability. The therapeutic drug, cisplatin decreases MdmX protein expression. USP2a mRNA and protein levels were also reduced after cisplatin exposure. The magnitude and time course of USP2a downregulation suggests that the reduction in USP2a levels could contribute to the decrease in MdmX expression following treatment with cisplatin. Knockdown of USP2a increases the sensitivity of NTERA-2 cells to cisplatin, raising the possibility that suppression of USP2a in combination with cisplatin may be an approach for cancer therapy.

show abstract

Section: Introductionsupporting

confidence: 78%

MdmX is a substrate for the deubiquitinating enzyme USP2a

et al. 2009

View full text Add to dashboard Cite

show abstract

“…The homologs are from the following species: Danio rerio (HN Soussi and May, 1996). Mdmx, a new member of the Mdm2 family was recently isolated and binds to p53, potentially in a manner similar to that by which Mdm2 binds (Shvarts et al, 1996). A p53-Mdm2 complex may even exist in invertebrates because the p53 homolog of squids contains an almost perfect conservation of the Mdm2 binding residues (P Winge and S Friend, unpublished observations cited in Soussi and May, 1996).…”

Section: Structure and Function Of Mdm2 Protein: The P53 Binding Domainmentioning

confidence: 99%

“…Mdm2 mRNA was detected in various adult tissues with higher levels in brain, muscle or testis (Fakharzadeh et al, 1991;Shvarts et al, 1996).…”

Section: Mdm2 and Terminal DI Erentiationmentioning

confidence: 99%

“…the in¯uence of the deletions on reproductive ®tness on one hand and the possible existence of compensatory pathways on the other. Perhaps relevant to the latter aspect is the recent discovery of Mdmx, an analog of Mdm2 (Shvarts et al, 1996;Shvarts et al, in press). However, important di erences may exist between Mdm2 and Mdmx.…”

Section: Mdm2 and Terminal DI Erentiationmentioning

confidence: 99%

See 1 more Smart Citation

Mdm2: keeping p53 under control

1997

View full text Add to dashboard Cite

The Mdm2 gene is overexpressed in several human tumors. The oncogenic potential of Mdm2 is partially explained by the inhibition of the activity of the tumor suppressor protein p53. Determination of the threedimensional structure of complexes between Mdm2 and the N-terminal p53 peptide provided a molecular basis for the inhibition of the transcriptional function of p53 by Mdm2. More dramatically, p53 is targeted by Mdm2 for rapid degradation. The Mdm2 gene itself is activated by p53, which gives the opportunity for feed-back control of p53 activity. Keeping p53 under control is most likely the major task of Mdm2 during early development. Recently, evidence was provided for an alternative, p53-independent function of Mdm2.

show abstract

“…Mdm4, a structural homologue of Mdm2, is also a critical regulator of p53 activity (Shvarts et al, 1996(Shvarts et al, , 1997. Unlike Mdm2, Mdm4 has no detectable ubiquitin ligase activity and is, therefore, unable to target p53 for degradation.…”

Section: Introductionmentioning

confidence: 99%

Role of Mdm4 in drug sensitivity of breast cancer cells

et al. 2010

View full text Add to dashboard Cite

The p53 tumor suppressor protein is frequently mutated in human tumors. It is thought that the p53 pathway is indirectly impaired in the remaining tumors, for example by overexpression of its important regulators Mdm2 and Mdm4, making them attractive targets for the development of anti-cancer agents. Recent studies have suggested that Mdm4 levels determine the sensitivity of tumor cells for anti-cancer therapy. To investigate this possibility, we studied the drug sensitivity of several breast cancer cell lines containing wild-type p53, but expressing different Mdm4 levels. We show that endogenous Mdm4 levels can affect the sensitivity of breast cancer cells to anti-cancer agents, but in a cell line-dependent manner and depending on an intact apoptotic response. Furthermore, treatment with the non-genotoxic agent Nutlin-3 sensitizes cells for doxorubicin, showing that activation of p53 by targeting its regulators is an efficient strategy to decrease cell viability of breast cancer cells. These results confirm a function of Mdm4 in determining the efficacy of chemotherapeutic agents to induce apoptosis of cancer cells in a p53-dependent manner, although additional undetermined factors also influence the drug response. Targeting Mdm4 to sensitize tumor cells for chemotherapeutic drugs might be a strategy to effectively treat tumors harboring wild-type p53.

show abstract

MDMX: a novel p53-binding protein with some functional properties of MDM2.

Cited by 566 publications

References 54 publications

MdmX is a substrate for the deubiquitinating enzyme USP2a

MdmX is a substrate for the deubiquitinating enzyme USP2a

Mdm2: keeping p53 under control

Role of Mdm4 in drug sensitivity of breast cancer cells

Contact Info

Product

Resources

About