The MDM2 RING-finger domain is required to promote p53 nuclear export

2000 ◽  
Vol 2 (9) ◽  
pp. 569-573 ◽  
Author(s):  
Rory K. Geyer ◽  
Zhong K. Yu ◽  
Carl G. Maki
Keyword(s):  
Nuclear Export ◽  
Ring Finger ◽  
Ring Finger Domain

scholarly journals MdmX Protects p53 from Mdm2-Mediated Degradation

2000 ◽  
Vol 20 (3) ◽  
pp. 1001-1007 ◽  
Author(s):  
Mark W. Jackson ◽  
Steven J. Berberich
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Nuclear Export ◽  
P53 Protein ◽  
Ring Finger ◽  
Ring Finger Domain ◽  
Cycle Arrest ◽  
Dependent Cell ◽  
Potential Basis ◽  
P53 Tumor Suppressor Protein

ABSTRACT The p53 tumor suppressor protein is stabilized in response to cellular stress, resulting in activation of genes responsible for either cell cycle arrest or apoptosis. The cellular pathway for releasing normal cells from p53-dependent cell cycle arrest involves the Mdm2 protein. Recently, a p53-binding protein with homology to Mdm2 was identified and called MdmX. Like Mdm2, MdmX is able to bind p53 and inhibit p53 transactivation; however, the ability of MdmX to degrade p53 has yet to be examined. We report here that MdmX is capable of associating with p53 yet is unable to facilitate nuclear export or induce p53 degradation. In addition, expression of MdmX can reverse Mdm2-targeted degradation of p53 while maintaining suppression of p53 transactivation. Using a series of MdmX deletions, we have determined that there are two distinct domains of the MdmX protein that can stabilize p53 in the presence of Mdm2. One domain requires MdmX interaction with p53 and results in the retention of both proteins within the nucleus and repression of p53 transactivation. The second domain involves the MdmX ring finger and results in stabilization of p53 and an increase in p53 transactivation. The potential basis for stabilization and increased p53 transactivation by the MdmX ring finger domain is discussed. Based on these observations, we propose that the MdmX protein may function to maintain a nuclear pool of p53 protein in undamaged cells.

scholarly journals Critical Contribution of the MDM2 Acidic Domain to p53 Ubiquitination

2003 ◽  
Vol 23 (14) ◽  
pp. 4939-4947 ◽  
Author(s):  
Hidehiko Kawai ◽  
Dmitri Wiederschain ◽  
Zhi-Min Yuan
Keyword(s):  
Nuclear Export ◽  
Critical Role ◽  
Ring Finger ◽  
E3 Ligase ◽  
Chimeric Protein ◽  
Chimeric Proteins ◽  
Ring Finger Domain ◽  
Acidic Domain ◽  
Ubiquitin E3 Ligase

ABSTRACT MDM2 is an E3 ubiquitin ligase that targets p53 for proteasomal degradation. Recent studies have shown, however, that the ring-finger domain (RFD) of MDM2, where the ubiquitin E3 ligase activity resides, is necessary but not sufficient for p53 ubiquitination, suggesting that an additional activity of MDM2 might be required. To test this possibility, we generated a series of MDM2/MDMX chimeric proteins to assess the contribution of each domain of MDM2 to the ubiquitination process. MDMX is a close structural homolog of MDM2 that nevertheless lacks the E3 ligase activity in vivo. We demonstrate here that MDMX gains self-ubiquitination activity and becomes extremely unstable upon introduction of the MDM2 RFD, indicating that the RFD is essential for self-ubiquitination. This MDMX chimeric protein, however, is unable to ubiquitinate p53 in vivo despite its E3 ligase activity and binding to p53, separating the self-ubiquitination activity of MDM2 from its ability to ubiquitinate p53. Significantly, fusion of the central acidic domain (AD) of MDM2 to the MDMX chimeric protein renders the protein fully capable of ubiquitinating p53, and p53 ubiquitination is associated with p53 degradation and nuclear export. Moreover, the AD mini protein expressed in trans can functionally rescue the AD-lacking MDM2 mutant, further supporting a critical role for the AD in MDM2-mediated p53 ubiquitination.

scholarly journals Normal Immune System Development in Mice Lacking the Deltex-1 RING Finger Domain

2005 ◽  
Vol 25 (4) ◽  
pp. 1437-1445 ◽  
Author(s):  
Sébastien Storck ◽  
Frédéric Delbos ◽  
Nicolas Stadler ◽  
Catherine Thirion-Delalande ◽  
Florence Bernex ◽  
...  
Keyword(s):  
B Cell ◽  
Notch Signaling ◽  
Ubiquitin Ligase ◽  
Cell Lineage ◽  
Ring Finger ◽  
Mouse Development ◽  
Ring Finger Domain ◽  
Ubiquitin Ligase Activity ◽  
Immune System Development ◽  
Cell Commitment

ABSTRACT The Notch signaling pathway controls several cell fate decisions during lymphocyte development, from T-cell lineage commitment to the peripheral differentiation of B and T lymphocytes. Deltex-1 is a RING finger ubiquitin ligase which is conserved from Drosophila to humans and has been proposed to be a regulator of Notch signaling. Its pattern of lymphoid expression as well as gain-of-function experiments suggest that Deltex-1 regulates both B-cell lineage and splenic marginal-zone B-cell commitment. Deltex-1 was also found to be highly expressed in germinal-center B cells. To investigate the physiological function of Deltex-1, we generated a mouse strain lacking the Deltex-1 RING finger domain, which is essential for its ubiquitin ligase activity. Deltex-1Δ/Δ mice were viable and fertile. A detailed histological analysis did not reveal any defects in major organs. T- and B-cell development was normal, as were humoral responses against T-dependent and T-independent antigens. These data indicate that the Deltex-1 ubiquitin ligase activity is dispensable for mouse development and immune function. Possible compensatory mechanisms, in particular those from a fourth Deltex gene identified during the course of this study, are also discussed.

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