p53 and MDM2: antagonists or partners in crime?
ABSTRACT Therapeutics that disrupt the p53-MDM2 interaction show promise for cancer treatment but surprisingly have different biological outcomes. A study by Enge et al. in this issue of Cancer Cell shows that the ability of MDM2 to target hnRNP K for degradation contributes to the decision to induce apoptosis rather than cell-cycle arrest.
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ABSTRACT: The tumor suppressor P53 and its negative regulator mouse double minute 2 (MDM2) play crucial roles in carcinogenesis. Previous case-control studies also revealed that P53 72Arg>Pro and MDM2 309T>G polymorphisms contribute to the risk of common cancers. However, the relationship between these two functional polymorphisms and adult acute lymphoblastic leukemia (ALL) susceptibility has not been explored. In this study, we performed a case-control study to explore the association between MDM2 and P53 gene polymorphisms and ALL risk in a Chinese population. We found an increased adult ALL risk associated with the MDM2 GG (odds ratio [OR]=2.79, 95% confidence interval [95% CI]=1.67-4.68) and TG (OR=1.49, 95% CI=0.95-2.53) genotypes. An increased risk associated with the P53 Pro/Pro genotype (OR=2.22, 95% CI=1.30-3.79) compared with the Arg/Arg genotype was also observed. Furthermore, the gene-gene interaction of MDM2 and P53 polymorphisms increased the adult ALL risk in a super-multiplicative manner (OR for the presence of both MDM2 GG and P53 Pro/Pro genotypes=8.05, 95% CI=2.53-25.58). These findings suggest that polymorphisms of MDM2 and P53 genes may be genetic modifiers for developing adult ALL.DNA and cell biology 06/2013; · 2.28 Impact Factor
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ABSTRACT: Murine double minute-2 (MDM2) is an intracellular molecule with multiple biologic functions. It serves as a negative regulator of p53 and thereby limits cell cycle arrest and apoptosis. Because MDM2 blockade suppresses tumor cell growth in vitro and in vivo, respective MDM2 inhibition is currently evaluated as anti-cancer therapy in clinical trials. However, the anti-proliferative effects of MDM2 inhibition also impair regenerative cell growth upon tissue injury. This was so far documented for tubular repair upon postischemic acute kidney injury and might apply to wound healing responses in general. Furthermore, MDM2 has numerous p53-independent effects. As a new entry, MDM2 was identified to act as a co-transcription factor for nuclear factor-kappa-light-enhancer of activated B cells (NF-κB) at cytokine promoters. This explains the potent anti-inflammatory effects of MDM2 inhibitors in vitro and in vivo. For example, the NF-κB-antagonistic and p53-agonistic activities of MDM2 inhibitors elicit potent therapeutic effects on experimental lymphoproliferative autoimmune disorders such as systemic lupus erythematosus. In this review, we discuss the classic p53-dependent, the recently discovered p53-independent, and the NF-κB-agonistic biologic functions of MDM2. We describe its complex regulatory role on p53 and NF-κB signaling and name areas of research that may help to foresee previously unexpected effects or potential alternative indications of therapeutic MDM2 blockade.Neoplasia (New York, N.Y.) 12/2012; 14(12):1097-101. · 5.48 Impact Factor
Article: Role of PET in Lymphoma.[Show abstract] [Hide abstract]
ABSTRACT: (18) F-2-deoxy-d-glucose positron emission tomography (FDG-PET), combined with a multidetector helical CT (PET/CT) has emerged, in the past decade as one of the most important prognostic tool for lymphoma management. Besides proving as the only imaging technique able to recapitulate all the information yielded by the standard radiological staging and restaging, it provided new essential information for chemosensitivity assessment and radiotherapy planning. In lymphoma staging, functional imaging (FI) by PET/CT was shown to be more accurate than conventional radiological (anatomical) imaging to detect nodal and extranodal involvement, whereas in posttreatment restaging it showed a superior predictive value on treatment outcome. In Hodgkin lymphoma (HL), FI concurred to delineate a new paradigm of therapy in which PET is considered an essential tool to guide physician's choice on treatment intensity and modality. In fact, PET proved very useful for: 1) assessing chemosensitivity early during treatment to predict final therapy outcome; 2) managing a residual mass, detected by CT scan in up to two thirds of patients at the end of chemotherapy; and 3) planning radiotherapy in early-stage disease when conformal radiotherapy fields are used to spare toxicity to adjacent tissues. The early chemosensitivity assessment is the underpinnings of a new therapeutic strategy in HL, aimed at minimizing treatment-related toxicity while maintaining treatment efficacy. Several clinical trials are currently underway to test this hypothesis. In diffuse, large, B-cell lymphoma (DLBCL), PET/CT proved very useful: 1) in lymphoma staging, leading to upward stage migration in one third of the patients; and 2) to identify patients benefiting from consolidation radiotherapy for FDG-avid, single mass or limited-extension disease. Different to HL, the role of interim PET in DLBCL remains controversial. In follicular lymphoma (FL) preliminary studies PET/CT proved useful, in baseline staging to predict time to treatment in patients in which a watchful observation without treatment (watch and wait) was chosen as therapeutic approach treatment. In FL end-of-treatment PET/CT proved the most powerful prognostic tool to predict long-term treatment outcome.Current Treatment Options in Oncology 03/2014; · 2.42 Impact Factor