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.
- SourceAvailable from: Ahmed M Kotb
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ABSTRACT: Murine double minute-2 (MDM2), an E3 ligase that regulates the cell cycle and inflammation, is highly expressed in podocytes. In podocyte injury, MDM2 drives podocyte loss by mitotic catastrophe, but the function of MDM2 in resting podocytes has not been explored. Here, we investigated the effects of podocyte MDM2 deletion in vitro and in vivo. In vitro, MDM2 knockdown by siRNA caused increased expression of p53 and podocyte death, which was completely rescued by coknockdown of p53. Apoptosis, pyroptosis, pyronecrosis, necroptosis, ferroptosis, and parthanatos were excluded as modes of occurrence for this p53-overactivationrelated cell death (here referred to as podoptosis). Podoptosis was associated with cytoplasmic vacuolization, endoplasmic reticulumstress, and dysregulated autophagy (previously described as paraptosis). MDM2 knockdown caused podocyte loss and proteinuria in a zebrafish model, which was consistent with the phenotype of podocyte-specific MDM2-knockout mice that also showed the aforementioned ultrastructual podocyte abnormalities before and during progressive glomerulosclerosis. The phenotype of both animal models was entirely rescued by codeletion of p53. We conclude that MDM2 maintains homeostasis and long-term survival in podocytes by preventing podoptosis, a p53-regulated form of cell death with unspecific features previously classified as paraptosis.
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