Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis

Iancu‐Rubin, Camelia; Mosoyan, Goar; Glenn, Kelli; Gordon, Ronald E.; Nichols, Gwen; Hoffman, Ronald

doi:10.1016/j.exphem.2013.11.012

Cited by 68 publications

(64 citation statements)

References 32 publications

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“…For the human progenitor retroviral transduction experiments enforcing IGF2BP3 expression, analyses were conducted on viable GFP + gated cells. Assessment of platelet release was conducted as previously described (38,39). Studies on transplanted mice were conducted 6 weeks after transplant.…”

Section: Discussionmentioning

confidence: 99%

“…These loss-of-function studies thus reveal an influence of IGF2BP3 levels on P-TEFb activation and megakaryocytic morphogenesis, consistent with a role as a critical ontogenic determinant. To address effects of IGF2BP3 knockdown on platelet production, a recently described ex vivo platelet-release assay (38,39) was applied to the culture system. Interpretation was complicated by the accelerated growth arrest and maturation associated with loss of IGF2BP3, but the studies supported an association between knockdown and enhanced platelet production on a per megakaryocyte basis (Supplemental Figure 10).…”

Section: Neonatal Megakaryocytes Display Decreased Morphogenesis Enhmentioning

confidence: 99%

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Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition

Elagib¹,

Lu²,

Mosoyan³

et al. 2017

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

Section: Neonatal Megakaryocytes Display Decreased Morphogenesis Enhmentioning

confidence: 99%

Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition

Elagib¹,

Lu²,

Mosoyan³

et al. 2017

Journal of Clinical Investigation

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“…In fact, in a recent exploratory clinical trial, the p53-activating molecule RG7112, a member of Nutlin family, has shown treatment-related serious adverse events (46), all of which related to haematologic toxicity (47) caused probably by the treatment-derived high levels of p53. Similarly, highly levels of p53 have been observed following the treatment with the unique double MDM2/MDM4 inhibitor developed so far (17).…”

Section: Discussionmentioning

confidence: 99%

Targeting the MDM2/MDM4 Interaction Interface as a Promising Approach for p53 Reactivation Therapy

et al. 2015

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Restoration of wild-type p53 tumor suppressor function has emerged as an attractive anticancer strategy. Therapeutics targeting the two p53-negative regulators, MDM2 and MDM4, have been developed, but most agents selectively target the ability of only one of these molecules to interact with p53, leaving the other free to operate. Therefore, we developed a method that targets the activity of MDM2 and MDM4 simultaneously based on recent studies indicating that formation of MDM2/MDM4 heterodimer complexes are required for efficient inactivation of p53 function. Using computational and mutagenesis analyses of the heterodimer binding interface, we identified a peptide that mimics the MDM4 C-terminus, competes with endogenous MDM4 for MDM2 binding, and activates p53 function. This peptide induces p53-dependent apoptosis in vitro and reduces tumor growth in vivo. Interestingly, interfering with the MDM2/ MDM4 heterodimer specifically activates a p53-dependent oxidative stress response. Consistently, distinct subcellular pools of MDM2/MDM4 complexes were differentially sensitive to the peptide; nuclear MDM2/MDM4 complexes were particularly highly susceptible to the peptide-displacement activity. Taken together, these data identify the MDM2/MDM4 interaction interface as a valuable molecular target for therapeutic reactivation of p53 oncosuppressive function.

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“…Hence, one of the key targets for cancer therapy is inactivation of the P53TAD-MDM2/MDMX contact by the small molecule MDM2 antagonist that maintain P53 by avoiding its interaction with MDM2 and selectively brings senescence in tumor cells. Some of these small-molecule MDM2 inhibitors, for example R7112 (Nutlin-3, analogs of cisimidazoline) and JNJ-26854165 (a tryptamine derivative) are now under clinical investigations [20,80,81] .…”

Section: Targeting P53mentioning

confidence: 99%

Apoptotic pathways as a therapeutic target for colorectal cancer treatment

Abraha

Ketema

2016

WJGO

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Colorectal cancer is the second leading cause of death from cancer among adults. The disease begins as a benign adenomatous polyp, which develops into an advanced adenoma with high-grade dysplasia and then progresses to an invasive cancer. Appropriate apoptotic signaling is fundamentally important to preserve a healthy balance between cell death and cell survival and in maintaining genome integrity. Evasion of apoptotic pathway has been established as a prominent hallmark of several cancers. During colorectal cancer development, the balance between the rates of cell growth and apoptosis that maintains intestinal epithelial cell homeostasis gets progressively disturbed. Evidences are increasingly available to support the hypothesis that failure of apoptosis may be an important factor in the evolution of colorectal cancer and its poor response to chemotherapy and radiation. The other reason for targeting apoptotic pathway in the treatment of cancer is based on the observation that this process is deregulated in cancer cells but not in normal cells. As a result, colorectal cancer therapies designed to stimulate apoptosis in target cells would play a critical role in controlling its development and progression. A better understanding of the apoptotic signaling pathways, and the mechanisms by which cancer cells evade apoptotic death might lead to effective therapeutic strategies to inhibit cancer cell proliferation with minimal toxicity and high responses to chemotherapy. In this review, we analyzed the current understanding and future promises of apoptotic pathways as a therapeutic target in colorectal cancer treatment.

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Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis

Cited by 68 publications

References 32 publications

Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition

Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition

Targeting the MDM2/MDM4 Interaction Interface as a Promising Approach for p53 Reactivation Therapy

Apoptotic pathways as a therapeutic target for colorectal cancer treatment

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