|Length matters: C-terminal tails regulate Mdm2-MdmX complexes.|
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|PMID: 22544075 Owner: NLM Status: MEDLINE|
|Masha V Poyurovsky|
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|Title: Cell cycle (Georgetown, Tex.) Volume: 11 ISSN: 1551-4005 ISO Abbreviation: Cell Cycle Publication Date: 2012 Apr|
|Created Date: 2012-04-30 Completed Date: 2012-09-14 Revised Date: 2013-06-25|
Medline Journal Info:
|Nlm Unique ID: 101137841 Medline TA: Cell Cycle Country: United States|
|Languages: eng Pagination: 1485 Citation Subset: IM|
|APA/MLA Format Download EndNote Download BibTex|
Protein Structure, Tertiary
Proto-Oncogene Proteins c-mdm2 / chemistry, metabolism*
Tumor Suppressor Protein p53 / metabolism
|0/Tumor Suppressor Protein p53; EC 188.8.131.52/Proto-Oncogene Proteins c-mdm2|
Journal ID (nlm-ta): Cell Cycle
Journal ID (iso-abbrev): Cell Cycle
Journal ID (publisher-id): CC
Publisher: Landes Bioscience
Copyright © 2012 Landes Bioscience
Print publication date: Day: 15 Month: 4 Year: 2012
pmc-release publication date: Day: 15 Month: 4 Year: 2012
Volume: 11 Issue: 8
First Page: 1485 Last Page: 1485
PubMed Id: 22544075
Publisher Id: 2012NV0631
Publisher Item Identifier: 20047
|Length matters : C-terminal tails regulate Mdm2–MdmX complexes|
|Masha V. Poyurovsky*|
|Kadmon Research Institute; New York, NY USA
|*Correspondence to: Masha V. Poyurovsky, Email: Masha@kadmon.com
Mechanisms controlling the p53 regulatory network remain the focus of numerous investigations in hopes of identifying more robust cancer therapies. Both Mdm2 and MdmX are found overexpressed in tumors with wild-type p53 and represent a key molecular device modulating p53 function. Thus, examining the interplay between these three proteins becomes highly relevant in the search for new pharmacological interventions in oncology.
Mdm2 is a RING-type E3 ubiquitin ligase capable of forming homo-oligomers and hetero-oligomerization with MdmX via the extreme C termini of their RING domains. Since its discovery 15 years ago, MdmX has been assigned many roles in the regulation of p53, either on its own or in concert with Mdm2. While clearly an essential negative regulator or p53 in development, its lack of intrinsic ubiquitin ligase activity has made the mechanism of p53 regulation more elusive than in the case of Mdm2. The capacity of MdmX to stimulate Mdm2-mediated p53 ubiquitination was first reported in 2003.1 Subsequent biochemical comparisons of the activity of Mdm2–MdmX complexes showed that not only does the presence of MdmX in the complex alter the substrate specificity of the holo-enzyme, it also allows for poly-ubiquitin chain formation on p53 (modification required for nuclear exclusion and degradation of p53).2-4
In vitro observations describing the importance of the MdmX RING domain in regulation of p53 turnover have now gained in vivo experimental support from the two knock-in animal models.5,6 Consistent with the notion that MdmX is an essential component of p53 polyubiquitination/proteasomal degradation pathway, mice expressing either a point mutant in the MdmX RING domain or a RING domain deletion mutant succumbed to a p53-dependent embryonic lethality. These data implicate the RING domain of MdmX as the sole region of importance in the ability of MdmX to regulate p53 and, by extension, the Mdm2-MdmX complex (and not the Mdm2 homodimer), as the principle negative regulator of p53 activity during development.
The growing body of evidence describing the presence of MdmX in the complex as crucial for target selectivity as well as the processivity of the holoezyme somewhat flies in the face of the existing structural data. Two published structures of the Mdm2 homodimer and Mdm2/MdmX heterodimer indicate virtually no difference in the complexes.7,8 In the absence of structural differences, how then are such significant differences in function accomplished?
A hypothesis unifying structural and functional data is brought forth by a very intriguing study from the Uldrijan group, which systematically looks at the differences between complex formation and activity of Mdm2 and MdmX.9 Phylogenetic analysis showed that the last cystein of the RING domain is followed by exactly 13 amino acids in all Mdm orthologs of vertebrate origin. Based on this, the authors hypothesized that not only the sequence of the C-terminal tails, but also their exact length are of central importance to the function of the complexes. Subsequent investigation of the ability of Mdm2 and MdmX proteins, which have been extended at the C terminus by 5, 14 or 18 amino acids, was designed to test the importance of the length of the C-terminal extensions. To the researchers surprise, when examined based on their ability to hetero-oligomerize and ubiquitinate p53, Mdm2 proteins behaved differently depending on whether the oligomeric partner was Mdm2 or MdmX.
Dolezelova et al. present unexpected experimental evidence for the heterocomplex being structurally and functionally distinct from the Mdm2 homodimer, while providing a mechanism for the observed in vivo functional differences between the complexes. Although the work casts slight doubt on the complete accuracy of the existing structures, it nicely aligns with the above-mentioned results, showing the singular importance of the MdmX RING domain in the activity of the holoenzyme. In light of these results, additional structural studies that will take in to account reported differences between the complexes will undoubtedly be informative and contribute to our understanding of the biochemistry of RING-type ubiquitin ligases and the mechanisms regulating p53 in cells.
Previously published online: www.landesbioscience.com/journals/cc/article/20047
|1.||Linares LK,et al. Proc Natl Acad Sci U S AYear: 2003100120091410.1073/pnas.203093010014507994|
|2.||Okamoto K,et al. FEBS LettYear: 20095832710410.1016/j.febslet.2009.07.02119619542|
|3.||Kawai H,et al. Cancer ResYear: 20076760263010.1158/0008-5472.CAN-07-131317616658|
|4.||Wang X,et al. J Biol ChemYear: 2011286237253410.1074/jbc.M110.21386821572037|
|5.||Huang L,et al. Proc Natl Acad Sci U S AYear: 201110812001610.103/pnas.110230910821730163|
|6.||Pant V,et al. Proc Natl Acad Sci U S AYear: 201110811995200010.1073/pnas.110224110821730132|
|7.||Kostic M,et al. J Mol BiolYear: 20063634335010.1016/j.jmb.2006.08.02716965791|
|8.||Linke K,et al. Cell Death DifferYear: 200815841810.1038/sj.cdd.440230918219319|
|9.||Dolezelova P,et al. Cell CycleYear: 2012119536210.4161/cc.11.5.1944522333590|
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