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Regulation of MDM4 (MDMX) Function by P76mdm2: a New Facet in the Control of P53 Activity

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Regulation of MDM4 (MDMX) Function by P76mdm2: a New Facet in the Control of P53 Activity Oncogene (2010) 29, 5935–5945 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc ORIGINAL ARTICLE Regulation of MDM4 (MDMX) function by p76MDM2: a new facet in the control of p53 activity S Giglio1,2,6, F Mancini1,2,6, M Pellegrino1, G Di Conza1,3, E Puxeddu4, A Sacchi5, A Pontecorvi2 and F Moretti1 1Institute of Neurobiology and Molecular Medicine, CNR/Fondazione Santa Lucia, Roma, Italy; 2Institute Medical Pathology, Catholic University, Roma, Italy; 3Department of Experimental-Clinical Medicine and Pharmacology, University of Messina, Messina, Italy; 4Department of Internal Medicine, University of Perugia, Perugia, Italy and 5Laboratory Molecular Oncogenesis, Regina Elena Cancer Institute, Roma, Italy Under basal growth conditions, p53 function is tightly viability. P53 basal activity is therefore strictly con- controlled by the members of MDM family, MDM2 and trolled to avoid unwarranted anomalies of cell growth. MDM4. The Mdm2 gene codes, in addition to the full-length Moreover, levels of p53 basal activity control the p90MDM2, for a short protein, p76MDM2 that lacks the p53- magnitude of its stress-induced biological responses, binding domain. Despite this property and at variance with including those raised by oncogenic stimuli (Wang et al., p90MDM2, this protein acts positively toward p53, although 2009). In normal growing cells, p53 is regulated in a the molecular mechanism remains elusive. Here, we report non-redundant manner by MDM family members, that p76MDM2 antagonizes MDM4 inhibitory function. We MDM4 and MDM2 (Marine et al., 2006). Although show that p76MDM2 possesses intrinsic ubiquitinating and contribution of each of these proteins has not yet been degrading activity, and through these activities controls completely resolved, their activity results in the control MDM4 levels. Furthermore, the presence of p76MDM2 of p53 levels and function. An exception in the MDM decreases the association of MDM4 with p53 and group is represented by p76MDM2, an MDM2 protein p90MDM2, and antagonizes p53 degradation by the hetero- that acts positively toward p53 (Perry et al., 2000). dimer MDM4/p90MDM2.Thep76MDM2-mediated regulation P76MDM2 derives from alternative translation of full- of MDM4 occurs in the cytoplasm, under basal growth length MDM2 mRNA. Indeed, MDM2, both human conditions. Conversely, upon DNA damage, phosphorylation and mouse, gives rise to two major proteins starting of MDM4Ser403 dissociates p76MDM2 and prevents MDM4 from two different AUGs and differing in molecular degradation. The overall negative control of MDM4 by weight, p90MDM2 and p76MDM2 (Saucedo et al., 1999; p76MDM2 reflects on p53 function as p76MDM2 impairs Cheng and Cohen, 2007). P90MDM2, the more abundant MDM4-mediated inhibition of p53 activity. In agreement form, binds p53 through its amino-terminus and withthepositiveroleofp76MDM2 toward p53, the p76MDM2/ controls both p53 protein levels, through its E3 p90MDM2 ratio significantly decreases in a group of thyroid ubiquitin ligase activity, as well as p53 transcriptional tumor samples compared with normal counterparts. Overall, function (Marine and Lozano, 2010). P76MDM2 lacks the these findings reveal a new mechanism in the control of p53 first N-terminal 49 amino acids, in which part of the basal activity that may account for the distinct sensitivity of p53-binding domain resides, and cannot bind p53. tissues to stress signals depending on the balance among Nonetheless, it is able to affect p53 activity by stabilizing MDM proteins. Moreover, these data suggest an onco- its protein levels and favoring its transcriptional suppressive function for a product of the Mdm2 gene. function (Perry et al., 2000). Thus far, p76MDM2 function Oncogene (2010) 29, 5935–5945; doi:10.1038/onc.2010.324; has been attributed to its ability to inhibit p90- published online 9 August 2010 degradative function, although neither association of p90MDM2 with p53 nor total levels of p90MDM2 result Keywords: p53; MDM4; MDM2; p76MDM2; p90MDM2 decreased by p76MDM2 (Perry et al., 2000). Despite the lack of a clear molecular function, in vivo data suggest that p76MDM2 represents an important MDM2 Introduction factor in the control of p53 activity. Indeed, p90 is more abundant than p76MDM2 in the brain, heart and MDM2 MDM2 The activation of the oncosuppressor p53 leads to kidney, whereas p76 and p90 are roughly different outcomes, all strongly affecting cell growth and equivalent in the spleen, thymus and intestine, tissues where p53 rapidly accumulate and is active in response to DNA damage (Perry et al., 2000). In addition, a Correspondence: Dr F Moretti, CNR-Institute of Neurobiology and recent report has shown increased expression of p76MDM2 Molecular Medicine, Via del Fosso di Fiorano, Roma 64-00143, Italy. associated with enhanced activity of p53 in the E-mail: [email protected] 6These authors contributed equally to this work. epidermal vitiligo lesions (Salem et al., 2009), suggesting MDM2 Received 10 December 2009; revised 14 May 2010; accepted 28 June a function for p76 in some pathological condi- 2010; published online 9 August 2010 tions too. p76MDM2 regulates p53 through control of MDM4 S Giglio et al 5936 MDM family includes MDM4 (also known as MDMX) too. MDM4 is an inhibitor of p53 activity under normal growth conditions (Marine et al., 2006; Wang et al., 2009), whereas it exerts a positive function toward p53-mediated apoptosis upon lethal DNA damage (Mancini and Moretti, 2009). Similar to p90MDM2, MDM4 inhibits p53 by controlling its protein levels and transcriptional function. However, MDM4 lacks E3 ubiquitin ligase activity and its ability to control p53 protein levels is mediated by heterodimer- ization with p90MDM2, which as a consequence acquires increased degradative potential toward p53 (Linares et al., 2003; Kawai et al., 2007; Linke et al., 2008; Okamoto et al., 2009). Although p76MDM2 shares with p90MDM2 the same protein domain at which levels MDM4 heterodimerizes, the function of p76MDM2 toward MDM4 in the regula- tion of p53 has not been investigated. In this work, we provide evidence that p76MDM2 antagonizes MDM4 activity. In particular, we show that p76MDM2 controls MDM4 protein levels by ubiqui- tinating and degrading it. Further, we showed that p76MDM2 impairs the association of MDM4 with p90MDM2 and p53, thereby reducing the degradative activity of the heterodimer toward p53. Most impor- tantly, the ratio of p76MDM2 to p90MDM2 levels was significantly decreased in a group of human thyroid tumors compared with matched normal tissues, sup- porting the role of p76MDM2-positive activity toward p53. Results P76MDM2 counteracts MDM4 activity on p53 independently of p90MDM2 P76MDM2, which does not bind p53, acts positively on p53 activity (Perry et al., 2000; Cheng and Cohen, 2007). P76MDM2 activity has been related to its ability to antagonize the degradative function of p90MDM2. Its relationship with MDM4 has not been investigated. Here, we tested the consequences of p76MDM2 expres- sion on MDM4-mediated inhibition of p53 transcrip- tional activity in Mdm2À/ÀMdm4À/Àp53À/ÀMEFs (TKO- MEFs). In agreement to that described previously, MDM4 inhibits p53 transactivating function, although less strongly than p90MDM2 (Figure 1a). The expression MDM2 of p76MDM2 per se did not alter p53 activity; however, it Figure 1 76 retrieves MDM4 inhibitory activity toward p53. (a) Transient transfection of Mdm4À/ÀMdm2À/Àp53À/ÀMEFs (TKO- partly prevented MDM4-mediated inhibition of p53 MEFs) with the indicated plasmids plus PG13Luc reporter and activity, indicating its ability to antagonize MDM4 b-gal plasmids. Cells were assayed 24 h after transfection. The data repression, independently of the presence of p90MDM2 are representative of two experiments performed in duplicate. (Figure 1a). In accordance with Perry’s work, p76MDM2 (b) qRT–PCR of p21 and Noxa mRNAs upon transient transfec- MDM2 tion of indicated plasmids. The data are representative of three antagonizes p90 -mediated inhibition of p53 too experiments. Bars represent the mean and line the standard (Perry et al., 2000). Similar results were obtained in deviation. (c) Western blot (WB) of indicated proteins in cell Mdm2À/Àp53À/ÀMEFs (DKO-MEFs) (data not shown). lysates collected from TKO-MEFs transiently transfected with Luciferase data were confirmed by quantitative real-time equimolar amounts of indicated plasmids. PCR (qRT–PCR) analysis of endogenous p21 and Noxa, two p53-induced targets in MEFs (Francoz The antagonism of p76MDM2 toward p90MDM2 has been et al., 2006). MDM4 represses moderately p53 activa- attributed to the inhibition of p90MDM2-mediated degra- tion of p21 and Noxa and p76MDM2 counteracts such dation of p53. However, MDM4 does not possess repression (Figure 1b). degradative function. Indeed, p53 protein levels did not Oncogene p76MDM2 regulates p53 through control of MDM4 S Giglio et al 5937 vary upon co-expression of p76MDM2 and MDM4 in fected with HA-Ub, MDM4, and p76MDM2 or p90MDM2, comparison with MDM4 alone (Figure 1c, lanes 6 and 5). and cell lysates immunoprecipitated with anti-HA anti- Conversely, MDM4 levels showed a strong decrease body (Figure 2b). In the presence of p76MDM2, there was associated with the expression of p76MDM2 independently a definite increase in MDM4 ubiquitinated forms of p53 (Figure 1c, compare lanes 6 and 5 with 7 and 1), associated with the downregulation of its levels. This suggesting that p76MDM2 activity toward p53 may be ubiquitination pattern was further enhanced
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