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MDM2 Promotes Ubiquitination and Degradation of MDMX

机译：MDM2促进MDMX的泛素化和降解

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The p53 tumor suppressor is regulated by MDM2-mediated ubiquitination and degradation. Mitogenic signals activate p53 by induction of ARF expression, which inhibits p53 ubiquitination by MDM2. Recent studies showed that the MDM2 homolog MDMX is also an important regulator of p53. We present evidence that MDM2 promotes MDMX ubiquitination and degradation by the proteasomes. This effect is stimulated by ARF and correlates with the ability of ARF to bind MDM2. Promotion of MDM2-mediated MDMX ubiquitination requires the N-terminal domain of ARF, which normally inhibits MDM2 ubiquitination of p53. An intact RING domain of MDM2 is also required, both to interact with MDMX and to provide E3 ligase function. Increase of MDM2 and ARF levels by DNA damage, recombinant ARF adenovirus infection, or inducible MDM2 expression leads to proteasome-mediated down-regulation of MDMX levels. Therefore, MDMX and MDM2 are coordinately regulated by stress signals. The ARF tumor suppressor differentially regulates the ability of MDM2 to promote p53 and MDMX ubiquitination and activates p53 by targeting both members of the MDM2 family.
机译：p53肿瘤抑制因子受MDM2介导的泛素化和降解调控。有丝分裂信号通过诱导ARF表达来激活p53，该表达抑制MDM2引起的p53泛素化。最近的研究表明，MDM2同源物MDMX也是p53的重要调节子。我们目前的证据，MDM2促进蛋白酶体的MDMX泛素化和降解。该作用被ARF刺激，并与ARF结合MDM2的能力有关。促进MDM2介导的MDMX泛素化需要ARF的N端结构域，该域通常会抑制p53的MDM2泛素化。还需要MDM2的完整RING域，以与MDMX交互并提供E3连接酶功能。 DNA损伤，重组ARF腺病毒感染或可诱导的MDM2表达导致MDM2和ARF水平升高，导致蛋白酶体介导的MDMX水平下调。因此，MDMX和MDM2受应力信号协调调节。 ARF肿瘤抑制因子通过靶向MDM2家族的两个成员来差异调节MDM2促进p53和MDMX泛素化的能力，并激活p53。

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