Scientific Background: MDM4 is a nuclear protein that contains a p53 binding domain at the N-terminus and a RING finger domain at the C-terminus. MDM4 shows structural similarity to p53-binding protein MDM2 and both proteins bind the p53 tumor suppressor protein and inhibit its activity. However, unlike MDM2, MDM4 does not cause nuclear export or degradation of p53. Instead, MDM4 inhibits p53 activity by binding to the transcriptional activation domain of p53. MDM4 is overexpressed in a variety of human cancers (1). Expression level of MDM4 is significantly higher in chronic lymphocytic leukemia. MDM4 is a specific chemotherapeutic target for treating retinoblastoma (2).
2. Laurie, N. A. et.al: Inactivation of the p53 pathway in retinoblastoma. Nature 444: 61-66, 2006.
NCBI and Uniprot Product Information
NCBI Description
This gene encodes a nuclear protein that contains a p53 binding domain at the N-terminus and a RING finger domain at the C-terminus, and shows structural similarity to p53-binding protein MDM2. Both proteins bind the p53 tumor suppressor protein and inhibit its activity, and have been shown to be overexpressed in a variety of human cancers. However, unlike MDM2 which degrades p53, this protein inhibits p53 by binding its transcriptional activation domain. This protein also interacts with MDM2 protein via the RING finger domain, and inhibits the latter's degradation. So this protein can reverse MDM2-targeted degradation of p53, while maintaining suppression of p53 transactivation and apoptotic functions. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Feb 2011]
Uniprot Description
Function: Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions. Ref.9 Ref.10
Subunit structure: Interacts with MDM2, TP53, TP73 and USP2. Found in a trimeric complex with UPB2, MDM2 and MDM4. Interacts (phosphorylated) with YWHAG; negatively regulates MDM4 activity toward TP53. Ref.9 Ref.10 Ref.11
Subcellular location: Nucleus.
Tissue specificity: Expressed in all tissues tested with high levels in thymus.
Induction: Down-regulated by cisplatin (at protein level). Ref.11
Domain: Region I is sufficient for binding TP53 and inhibiting its G1 arrest and apoptosis functions. It also binds TP73. Region II contains most of a central acidic region and a putative C4-type zinc finger. The RING finger domain which coordinates two molecules of zinc mediates the heterooligomerization with MDM2.
Post-translational modification: Phosphorylated. Phosphorylation at Ser-367 promotes interaction with YWHAG and subsequent ubiquitination and degradation. Phosphorylation at Ser-342 also induces ubiquitination and degradation but to a lower extent. Ref.9 Ref.10Ubiquitinated and degraded by MDM2. Deubiquitination by USP2 on the other hand stabilizes the MDM4 protein. Ref.9 Ref.11
Sequence similarities: Belongs to the MDM2/MDM4 family.Contains 1 RanBP2-type zinc finger.Contains 1 RING-type zinc finger.Contains 1 SWIB domain.
Mass spectrometry: Molecular mass is 54863.3 Da from positions 1 - 490. Determined by MALDI. Ref.12
Research Articles on MDM4
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Product Notes
The MDM4 mdm4 (Catalog #AAA515348) is a Recombinant Protein produced from E Coli and is intended for research purposes only. The product is available for immediate purchase. The immunogen sequence is 1-137 with tag His tag!!Expression System||E.coli!!Source Note||Recombinant human MDM4 (1-137) was expressed in E. coli cells. AAA Biotech's MDM4 can be used in a range of immunoassay formats including, but not limited to, Western Blot (WB). Researchers should empirically determine the suitability of the MDM4 mdm4 for an application not listed in the data sheet. Researchers commonly develop new applications and it is an integral, important part of the investigative research process. It is sometimes possible for the material contained within the vial of "MDM4, Recombinant Protein" to become dispersed throughout the inside of the vial, particularly around the seal of said vial, during shipment and storage. We always suggest centrifuging these vials to consolidate all of the liquid away from the lid and to the bottom of the vial prior to opening. Please be advised that certain products may require dry ice for shipping and that, if this is the case, an additional dry ice fee may also be required.Precautions
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