Search results for MDM4

Showing 25 results out of 33

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Species

Types

Compartments

Reaction types

Search properties

Protein (5 results from a total of 5)

Identifier: R-HSA-349430
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: MDM4: O15151
Identifier: R-HSA-6782502
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: MDM4: O15151
Identifier: R-HSA-349461
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: MDM4: O15151
Identifier: R-HSA-349441
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: O15151
Identifier: R-HSA-6804938
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: O15151

Reaction (6 results from a total of 9)

Identifier: R-HSA-6804724
Species: Homo sapiens
Compartment: nucleoplasm
Once MDM4 is phosphorylated by ATM and CHEK2 in response to DNA damage, MDM2 ubiquitinates MDM4 and targets it for degradation (Chen et al. 2005, Pereg et al. 2005). The presence of MDM4 stimulates auto-ubiquitination of MDM2 (Linares et al. 2003).
Identifier: R-HSA-349426
Species: Homo sapiens
Compartment: nucleoplasm
CHEK2 (Chk2) kinase is required for phosphorylation of MDM4 at serine residues S342 and S367 in vivo. CHEK2-mediated phosphorylation stimulates MDM4 ubiquitination by MDM2 and subsequent degradation (Chen et al. 2005).
Identifier: R-HSA-349455
Species: Homo sapiens
Compartment: nucleoplasm
Human MDM4 (MDMX) is phosphorylated on serine residue S403 by ATM. This site is important for MDM2-mediated ubiquitination of MDM4 after induction of double strand DNA breaks (Pereg et al. 2005, Chen et al. 2005).
Identifier: R-HSA-6805022
Species: Homo sapiens
Compartment: nucleoplasm
The ubiquitin protease USP2 forms a tripartite complex with MDM2 and MDM4 (MDMX) by binding to the ubiquitinated heterodimer of MDM2 and MDM4 (Allende-Vega et al. 2010).
Identifier: R-HSA-5689972
Species: Homo sapiens
Compartment: nucleoplasm
The ubiquitin protease USP2 deubiquitinates MDM2 and MDM4 but not TP53 (Stevenson et al. 2007, Allende-Vega et al. 2010).
Identifier: R-HSA-5689950
Species: Homo sapiens
Compartment: nucleoplasm
USP7 (HAUSP) is able to deubiquitinate many substrates. It is a key regulator of the tumor suppressor TP53 (p53) (Vousden & Lu 2002). It can act on TP53 directly, or indirectly by acting on the E3 ligase MDM2, which can ubiquitinate TP53 (Chene 2003, Li et al. 2002, 2004, Kon et al. 2010). USP7 also regulates MDM4 (Mdmx), a structural homolog of MDM2 (Meulmeester et al. 2005, Chen 2012). USP7 interacts with and deubiquitinates FOXO4 in response to oxidative stress (van der Horst et al. 2006) and reduces monoubiquitinylation of PTEN, presumably on the previously identified lysine residues 13 and 289 (Trotman et al. 2007), reducing nuclear PTEN levels (Song et al. 2008).

Complex (6 results from a total of 11)

Identifier: R-HSA-6804932
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-6804939
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-6804936
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-6782656
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-6782767
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-6804885
Species: Homo sapiens
Compartment: nucleoplasm

Set (6 results from a total of 6)

Identifier: R-HSA-6804750
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-5689977
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-6804745
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-6805030
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-6782516
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-6805029
Species: Homo sapiens
Compartment: nucleoplasm

Pathway (2 results from a total of 2)

Identifier: R-HSA-6806003
Species: Homo sapiens
TP53 (p53) tumor suppressor protein is a transcription factor that functions as a homotetramer (Jeffrey et al. 1995). The protein levels of TP53 are low in unstressed cells due to MDM2-mediated ubiquitination that triggers proteasome-mediated degradation of TP53 (Wu et al. 1993). The E3 ubiquitin ligase MDM2 functions as a homodimer/homo-oligomer or a heterodimer/hetero-oligomer with MDM4 (MDMX) (Linares et al. 2003, Toledo and Wahl 2007, Cheng et al. 2011, Wade et al. 2013).

Activating phosphorylation of TP53 at serine residues S15 and S20 in response to genotoxic stress disrupts TP53 interaction with MDM2. In contrast to MDM2, E3 ubiquitin ligases RNF34 (CARP1) and RFFL (CARP2) can ubiquitinate phosphorylated TP53 (Yang et al. 2007). Binding of MDM2 to TP53 is also inhibited by the tumor suppressor p14-ARF, transcribed from the CDKN2A gene in response to oncogenic signaling or oxidative stress (Zhang et al. 1998, Parisi et al. 2002, Voncken et al. 2005). Ubiquitin-dependant degradation of TP53 can also be promoted by PIRH2 (Leng et al. 2003) and COP1 (Dornan et al. 2004) ubiquitin ligases. HAUSP (USP7) can deubiquitinate TP53, contributing to TP53 stabilization (Li et al. 2002).

While post-translational regulation plays a prominent role, TP53 activity is also controlled at the level of promoter function (reviewed in Saldana-Meyer and Recillas-Targa 2011), mRNA stability and translation efficiency (Mahmoudi et al. 2009, Le et al. 2009, Takagi et al. 2005).

Identifier: R-HSA-6804757
Species: Homo sapiens
In unstressed cells, TP53 (p53) has a short half-life as it undergoes rapid ubiquitination and proteasome-mediated degradation. The E3 ubiquitin ligase MDM2, which is a transcriptional target of TP53, plays the main role in TP53 protein down-regulation (Wu et al. 1993). MDM2 forms homodimers and homo-oligomers, but also functions as a heterodimer/hetero-oligomer with MDM4 (MDMX) (Sharp et al. 1999, Cheng et al. 2011, Huang et al. 2011, Pant et al. 2011). The heterodimers of MDM2 and MDM4 may be especially important for downregulation of TP53 during embryonic development (Pant et al. 2011).

The nuclear localization of MDM2 is positively regulated by AKT- or SGK1- mediated phosphorylation (Mayo and Donner 2001, Zhou et al. 2001, Amato et al. 2009, Lyo et al. 2010). Phosphorylation of MDM2 by CDK1 or CDK2 decreases affinity of MDM2 for TP53 (Zhang and Prives 2001). ATM and CHEK2 kinases, activated by double strand DNA breaks, phosphorylate TP53, reducing its affinity for MDM2 (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998, Chehab et al. 1999, Chehab et al. 2000). At the same time, ATM phosphorylates MDM2, preventing MDM2 dimerization (Cheng et al. 2009, Cheng et al. 2011). Both ATM and CHEK2 phosphorylate MDM4, triggering MDM2-mediated ubiquitination of MDM4 (Chen et al. 2005, Pereg et al. 2005). Cyclin G1 (CCNG1), transcriptionally induced by TP53, targets the PP2A phosphatase complex to MDM2, resulting in dephosphorylation of MDM2 at specific sites, which can have either a positive or a negative impact on MDM2 function (Okamoto et al. 2002).

In contrast to MDM2, E3 ubiquitin ligases RNF34 (CARP1) and RFFL (CARP2) can ubiquitinate phosphorylated TP53 (Yang et al. 2007).

In addition to ubiquitinating MDM4 (Pereg et al. 2005), MDM2 can also undergo auto-ubiquitination (Fang et al. 2000). MDM2 and MDM4 can be deubiquitinated by the ubiquitin protease USP2 (Stevenson et al. 2007, Allende-Vega et al. 2010). The ubiquitin protease USP7 can deubiquitinate TP53, but in the presence of DAXX deubiquitinates MDM2 (Li et al. 2002, Sheng et al. 2006, Tang et al. 2006).

The tumor suppressor p14-ARF, expressed from the CDKN2A gene in response to oncogenic or oxidative stress, forms a tripartite complex with MDM2 and TP53, sequesters MDM2 from TP53, and thus prevents TP53 degradation (Zhang et al. 1998, Parisi et al. 2002, Voncken et al. 2005).

For review of this topic, please refer to Kruse and Gu 2009.

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