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  • 1
    Keywords: APOPTOSIS ; CELLS ; proliferation ; tumor ; BLOOD ; CELL ; IN-VIVO ; INHIBITION ; DEATH ; liver ; DISTINCT ; DIFFERENTIATION ; MICE ; CONTRAST ; p53 ; PHENOTYPE ; CYCLOPHOSPHAMIDE ; EMBRYONIC LETHALITY ; REGULATOR ; STAT5A(-/-)5B(-/-) MICE ; COLONY-STIMULATING FACTOR ; PROGRAM ; TUMOR-SUPPRESSOR ; LINEAGE ; LEVEL ; ROLES ; PHASE ; function ; P53 ACTIVITY ; ERYTHROPOIESIS ; ERYTHROID PROGENITORS ; MDM4-NULL MICE
    Abstract: Mdm2 and Mdm4 are critical negative regulators of the p53 tumor suppressor. Mdm4-null mutants are severely anemic and exhibit impaired proliferation of the fetal liver erythroid lineage cells. This phenotype may indicate a cell-intrinsic function of Mdm4 in erythropoiesis. In contrast, red blood cell count was nearly normal in mice engineered to express low levels of Mdm2, suggesting that Mdm2 might be dispensable for red cell production. Here, we further explore the tissue-specific functions of Mdm2 and Mdm4 in the erythroid lineage by intercrossing conditional Mdm4 and Mdm2 alleles to an erythroid-specific Cre (Er-GFP-Cre) knock-in allele. Our data show that Mdm2 is required for rescuing erythroid progenitors from p53-mediated apoptosis during primitive erythropoiesis. In contrast, Mdm4 is only required for the high erythropoietic rate during embryonic definitive erythropoiesis. Thus, in this particular cellular context, Mclm4 only contributes to p53 regulation at a specific phase of the differentiation program
    Type of Publication: Journal article published
    PubMed ID: 17105817
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  • 2
    Keywords: LINES ; FREQUENCY ; INDUCED APOPTOSIS ; GENE-MUTATIONS ; WILD-TYPE P53 ; NUCLEAR ; CYTOPLASMIC SEQUESTRATION ; SENSITIZES NEUROBLASTOMA ; ARF TUMOR-SUPPRESSOR ; P53/MDM2/P14(ARF) PATHWAY
    Abstract: Suppression of p53 activity is essential for proliferation and survival of tumor cells. A direct p53-activating compound, nutlin-3, was used in this study, together with p53 mutation analysis, to characterize p53 pathway defects in a set of 34 human neuroblastoma cell lines. We identified 9 cell lines (26%) with a p53 loss-of-function mutation, including 6 missense mutations, 1 nonsense mutation, 1 in-frame deletion, and 1 homozygous deletion of the 30 end of the p53 gene. Sensitivity to nutlin-3 was highly predictive of absence of p53 mutation. Signaling pathways downstream of p53 were functionally intact in 23 of 25 cell lines with wild-type p53. Knockdown and overexpression experiments revealed a potentiating effect of p14(ARF) expression on the response of neuroblastoma cells to nutlin-3. Our findings shed light on the spectrum of p53 pathway lesions in neuroblastoma cells, indicate that defects in effector molecules downstream of p53 are remarkably rare in neuroblastoma, and identify p14(ARF) as a determinant of the outcome of the response to MDM2 inhibition. These insights may prove useful for the clinical translation of evolving strategies aimed at p53 reactivation and for the development of new therapeutic approaches.
    Type of Publication: Journal article published
    PubMed ID: 21460101
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