MDM2 interacts with MDMX through their RING finger domains

Tanimura, Shyu; Ohtsuka, Satoshi; Mitsui, Kiyofumi; Shirouzu, Kazuo; Yoshimura, Akihiko; Ohtsubo, Motoaki

doi:10.1016/s0014-5793(99)00254-9

Cited by 285 publications

(317 citation statements)

References 26 publications

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“…RBDs reported appear to be speci®c to certain RINGs where RINGs from other proteins are unable to interact. Alternatively, certain RING proteins bind selected RING proteins through their respective RINGs (Tanimura et al, 1999;Meza et al, 1999). Outside of RING RING interactions, the proline-rich region of PRH is the ®rst RBD that recognizes more than one RING.…”

Section: Discussionmentioning

confidence: 99%

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The promyelocytic leukemia protein PML interacts with the proline-rich homeodomain protein PRH: a RING may link hematopoiesis and growth control

et al. 1999

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Acute promyelocytic leukemia (APL) is characterized by a block in myeloid cell di erentiation. As a result of a chromosomal translocation in these patients, the promyelocytic leukemia protein PML is disrupted as are the nuclear bodies it forms. Disruption of PML and PML nuclear bodies in APL is linked to a loss of growth control and subsequent leukemogenesis. PML contains a zinc-binding domain known as the RING which is required for formation of these bodies. Using yeast 2-hybrid techniques, we found that PML and a related RING protein, Z, bind the proline rich homeodomain protein (PRH) through their RING domains. Previous reports indicate that PRH functions in hematopoiesis and may act as a transcriptional repressor. Our data indicate that PML and Z both bind the repressor domain of PRH and are the ®rst protein partners reported for PRH. We observe that PRH has a punctate pattern in both the nucleus and cytoplasm of chronic myelogenous leukemia K562 cells and in the APL cell line, NB4. Immunoprecipitation and co-localization studies indicate that PML and PRH interact in both cell lines. The e ect on cell growth by PML and the hematopoietic actions of PRH raises the possibility that the interaction between PML and PRH represents a link between growth control and hematopoiesis.

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Section: Discussionmentioning

confidence: 99%

“…Previous reports show that RING proteins can bind other RING proteins through this domain (e.g. Tanimura et al, 1999;Meza et al, 1999). Others report that the RING can bind ubiquitin like molecules and ubiquitin hydrolase molecules (Jensen et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

The promyelocytic leukemia protein PML interacts with the proline-rich homeodomain protein PRH: a RING may link hematopoiesis and growth control

et al. 1999

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“…The novel function does not appear to be binding to RNA (Elenbaas et al, 1996), since mutants with di erent e ects on cell cycle bind RNA with similar a nity (poly-G agarose beads, data not shown). The MDM2 RING ®nger has been reported to bind to TAF II 250 (Leveillard and Wasylyk, 1997) and MDMX (Sharp et al, 1999;Tanimura et al, 1999). It may also interact with speci®c E2s, in analogy with a number of RING ®nger proteins that have recently been shown to have E3 ubiquitin ligase activity and to bind to E2 ubiquitin conjugating enzymes (Hu and Fearon, 1999;Joazeiro et al, 1999;Lorick et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

The contribution of the RING finger domain of MDM2 to cell cycle progression

Argentini¹,

Barboule²,

Wasylyk³

2000

Oncogene

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The MDM2 oncoprotein binds to p53 and abrogates p53-mediated G1 arrest and apoptosis. We show that MDM2 over-expression accelerates cell cycle progression of RPMI2650 cells by overcoming the negative e ect of endogenous wild type p53 at the G1/S checkpoint. The interaction with p53 and transcription inhibition are necessary but not su cient. The RING ®nger domain of MDM2 is also required for the positive e ect of MDM2 on the cell cycle. Surprisingly, several point mutants in the zinc binding sites of the RING ®nger are fully competent for cell cycle stimulation even though they abolish MDM2-directed degradation of p53 and MDM2 E3-ligase activity. In contrast, alterations in and around the cryptic nucleolar localization sequence (KR motif) inhibit MDM2-mediated cell cycle progression as well as p53 degradation and MDM2 E3 ligase activity. We found that all the RING mutants decrease inhibition of both p53 dependent reporters and endogenous p21 CIP1/WAF1/SDI1 . These results indicate that the RING ®nger of MDM2 has a role in the regulation of the cell cycle that is independent of p53 degradation and endogenous p21 CIP1/WAF1/SDI1 regulation. Oncogene (2000) 19, 3849 ± 3857.

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“…Mdm2 and MdmX hetero-oligomerize through their C-terminal RING finger domains (Tanimura et al, 1999). To determine whether Mdm2 competes for binding of USP2a to MdmX, a GST pull down assay was carried out.…”

Section: Usp2a Forms a Complex With Mdmxmentioning

confidence: 99%

“…It has also been suggested that MdmX may regulate the stability of p53 indirectly. Mdm2 and MdmX interact through their RING fingers and this interaction can stabilize Mdm2 and promote Mdm2-mediated degradation of p53 (Tanimura et al, 1999;Gu et al, 2002). However, in mice MdmX knockout increases p53 transcriptional activity but has little or no effect on p53 levels (Marine et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

MdmX is a substrate for the deubiquitinating enzyme USP2a

et al. 2009

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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.

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MDM2 interacts with MDMX through their RING finger domains

Cited by 285 publications

References 26 publications

The promyelocytic leukemia protein PML interacts with the proline-rich homeodomain protein PRH: a RING may link hematopoiesis and growth control

The promyelocytic leukemia protein PML interacts with the proline-rich homeodomain protein PRH: a RING may link hematopoiesis and growth control

The contribution of the RING finger domain of MDM2 to cell cycle progression

MdmX is a substrate for the deubiquitinating enzyme USP2a

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