Distinct roles of Mdm2 and Mdm4 in red cell production

Maetens, Marion; Doumont, Gilles; Clercq, Sarah De; Francoz, Sarah; Froment, Pascal; Bellefroid, Éric; Klingmüller, Ursula; Lozano, Guillermina; Marine, Jean–Christophe

doi:10.1182/blood-2006-03-013656

Cited by 65 publications

(63 citation statements)

References 23 publications

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“…Previous reports have attempted to link Notch induction of apoptosis through the p53 pathway in other systems. 36,37 We have also explored that possibility in erythroid cells, since there is increasing evidence of p53-mediated apoptosis at different stages of erythroid differentiation; 13,38 however, our results show that crucial p53 pathway genes are not affected in the RBPjk À/À erythroid cells suggesting that this pathway is not responsible for the protection of apoptosis in the RBPjk mutants. In fact, we found an erythroid-specific upregulation of the proapoptotic p53-target gene, puma, in the RBPjk À/À Ter119 þ cells, which is surprising since this population has a lower apoptotic rate.…”

Section: Discussioncontrasting

confidence: 41%

The notch pathway positively regulates programmed cell death during erythroid differentiation

et al. 2007

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Programmed cell death plays an important role in erythropoiesis under physiological and pathological conditions. In this study, we show that the Notch/RBPjj signaling pathway induces erythroid apoptosis in different hematopoietic tissues, including yolk sac and bone marrow as well as in murine erythroleukemia cells. In RBPjj À/À yolk sacs, erythroid cells have a decreased rate of cell death that results in increased number of Ter119 þ cells. A similar effect is observed when Notch activity is abrogated by incubation with the c-secretase inhibitors, DAPT or L685,458. We demonstrate that incubation with Jagged1-expressing cells has a proapoptotic effect in erythroid cells from adult bone marrow that is prevented by blocking Notch activity. Finally, we show that the sole expression of the activated Notch1 protein is sufficient to induce apoptosis in hexametilene-bisacetamide-differentiating murine erythroleukemia cells. Together these results demonstrate that Notch regulates erythroid homeostasis by inducing apoptosis.

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Section: Discussioncontrasting

confidence: 41%

The notch pathway positively regulates programmed cell death during erythroid differentiation

et al. 2007

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“…A role of MDM2/p53 in the regulation of erythropoiesis has been suggested by the defects in early and late erythropoiesis observed in mice with a conditional knockout of MDM2 (Maetens et al, 2007). Noteworthy, the pathogenesis of the anemia in 5q-and Diamond-Blackfan syndromes could be related to p53 induction by a ribosomal stress (Sieff et al, 2010), whereas p53 is downregulated by oncogenes such as Fli-1 or PU1/Spi-1 in erythroleukemia (Wong et al, 1999;Scolan et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

JAK2V617F negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms

et al. 2011

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JAK2 V617F is a gain of function mutation that promotes cytokine-independent growth of myeloid cells and accounts for a majority of myeloproliferative neoplasms (MPN). Mutations in p53 are rarely found in these diseases before acute leukemia transformation, but this does not rule out a role for p53 deregulation in disease progression. Using Ba/ F3-EPOR cells and ex vivo cultured CD34 þ cells from MPN patients, we demonstrate that expression of JAK2 V617F affected the p53 response to DNA damage. We show that E3 ubiquitin ligase MDM2 accumulated in these cells, due to an increased translation of MDM2 mRNA. Accumulation of the La autoantigen, which interacts with MDM2 mRNA and promotes its translation, was responsible for the increase in MDM2 protein level and the subsequent degradation of p53 after DNA damage. Downregulation of La protein or cell treatment with nutlin-3, a MDM2 antagonist, restored the p53 response to DNA damage and the cytokine-dependence of Ba/F3-EPOR-JAK2 V617F cells. Altogether, these data indicate that the JAK2 V617F mutation affects p53 response to DNA damage through the upregulation of La antigen and accumulation of MDM2. They also suggest that p53 functional inactivation accounts for the cytokine hypersensitivity of JAK2 V617F MPN and might have a role in disease progression.

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“…A recent analysis of the p53 response to ribosomal stress in HCT116 and U2OS cells is also consistent with this model . Thus, this regulation model applies to many tissues, although it remains possible that the relative contribution of MDM2 and MDM4 to p53 regulation varies in some tissues or during specific differentiation phases (discussed in (Marine et al, 2006;Boesten et al, 2006;Maetens et al, 2007). Importantly, a direct implication of the regulation model is that p53 stability and activity are regulated in distinct ways, a notion further supported by the recent analysis of a p53 mouse mutant with point mutations in the proline-rich domain (Toledo et al, 2007).…”

Section: Biological Functionsmentioning

confidence: 96%

MDM2 and MDM4: p53 regulators as targets in anticancer therapy

Toledo

Wahl

2007

The International Journal of Biochemistry & Cell Biology

215

162

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The gene TP53, encoding transcription factor p53, is mutated or deleted in half of human cancers, demonstrating the crucial role of p53 in tumor suppression. Importantly, p53 inactivation in cancers can also result from the amplification / overexpression of its specific inhibitors MDM2 and MDM4 (also known as MDMX). The presence of wild-type p53 in those tumors with MDM2 or MDM4 overexpression stimulates the search for new therapeutic agents to selectively reactivate it. This short survey highlights recent insights into MDM2 and MDM4 regulatory functions and their implications for the design of future p53-based anticancer strategies. We now know that MDM2 and MDM4 inhibit p53 in distinct and complementary ways: MDM4 regulates p53 activity, while MDM2 mainly regulates p53 stability. Upon DNA damage, MDM2-dependent degradation of itself and MDM4 contribute significantly to p53 stabilization and activation. These and other data imply that the combined use of MDM2 and MDM4 antagonists in cancer cells expressing wild type p53 should activate p53 more significantly than agents that only antagonize MDM2, resulting in more effective anti-tumor activity.

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Distinct roles of Mdm2 and Mdm4 in red cell production

Cited by 65 publications

References 23 publications

The notch pathway positively regulates programmed cell death during erythroid differentiation

The notch pathway positively regulates programmed cell death during erythroid differentiation

JAK2V617F negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms

MDM2 and MDM4: p53 regulators as targets in anticancer therapy

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