Zebrafish as a Model Organism for the Identification and Characterization of Drugs and Genes Affecting p53 Signaling

Langheinrich, Ulrike; Hennen, Elisabeth; Stott, Gordon M.; Vacun, Gabi

doi:10.1016/s0960-9822(02)01319-2

Cited by 352 publications

(329 citation statements)

References 21 publications

(1 reference statement)

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“…(The p53 M214K mutation is in the DNA binding domain.) We used gamma-radiation to activate p53, as radiation is an insult that is known to activate the p53 pathway[33]. We have previously shown that the p53 mutant no longer up-regulates p21 in response to irradiation[22].…”

Section: Resultsmentioning

confidence: 99%

Hematopoietic defects in rps29 mutant zebrafish depend upon p53 activation

Taylor

Humphries

White

et al. 2012

Experimental Hematology

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Disruption of ribosomal proteins is associated with hematopoietic phenotypes in cell culture and animal models. Mutations in ribosomal proteins are seen in patients with Diamond Blackfan anemia (DBA), a rare congenital disease characterized by red cell aplasia and distinctive craniofacial anomalies. A zebrafish screen uncovered decreased hematopoietic stem cells (HSCs) in embryos with mutations in ribosomal protein rps29. Here, we determined that rps29-/- embryos also have red blood cell defects and increased apoptosis in the head. As the p53 pathway has been shown to play a role in other ribosomal protein mutants, we studied the genetic relationship of rps29 and p53. Transcriptional profiling revealed that genes up-regulated in the rps29 mutant are enriched for genes up-regulated by p53 after irradiation. p53 mutation near completely rescues the rps29 morphological and hematopoietic phenotypes, demonstrating that p53 mediates the effects of rps29 knockdown. We also identified neuronal gene orthopedia protein a (otpa) as one whose expression correlates with rps29 expression, suggesting that levels of expression of some genes are dependent on rps29 levels. Together, our studies demonstrate a role of p53 in mediating the cellular defects associated with rps29 and establish a role for rps29 and p53 in HSCs and red blood cell development.

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Section: Resultsmentioning

confidence: 99%

Hematopoietic defects in rps29 mutant zebrafish depend upon p53 activation

Taylor

Humphries

White

et al. 2012

Experimental Hematology

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“…RhoA knockdown induces apoptosis during zebrafish embryogenesis It is reported that the opaque regions in the developing zebrafish embryos implicate cell death and could be a consequence of apoptosis (Langheinrich et al, 2002). To examine this, we analysed the phenotypic embryos by TUNEL assay.…”

Section: Resultsmentioning

confidence: 99%

RhoA prevents apoptosis during zebrafish embryogenesis through activation of Mek/Erk pathway

et al. 2007

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RhoA small GTPase, as a key regulator for actin cytoskeletal rearrangement, plays pivotal roles during morphogenesis, cytokinesis, phagocytosis and cell migration, but little is known about its signaling mechanism that controls cell survival in vivo. Using zebrafish as a model, we show that non-overlapping antisense morpholinos that block either translation or splicing of rhoA lead to extensive apoptosis during embryogenesis, resulting in overall reduction of body size and body length. These defects are associated with reduced activation of growth-promoting Erk and decreased expression of anti-apoptotic bcl-2. Moreover, ectopic expression of rhoA, Mek or BCL-2 mRNA rescues such phenotypes. Consistently, combined suppression of RhoA and Mek/Erk or Bcl-2 pathways by sub-optimal dose of rhoA morpholino and pharmacological inhibitors for either Mek (U0126) or Bcl-2 (HA 14-1) can induce developmental abnormalities and enhanced apoptosis, similar to those caused by effective RhoA knockdown. Furthermore, U0126 abrogates the rescue by RhoA and MEK but not BCL-2. In contrast, HA 14-1 effectively abolishes all functional rescues by RhoA, MEK or BCL-2, supporting that RhoA prevents apoptosis by activation of Mek/Erk pathway and requiring Bcl-2. These findings reveal an important genetic and functional relationship between RhoA with Mek/Erk and Bcl-2 for cell survival control during embryogenesis.

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“…In zebrafish, CPT induces p53 activation and causes apoptosis (Langheinrich et al, 2002;Le et al, 2009). Therefore, we tested whether MLL5-mediated p53 activation by CPT was conserved in developing zebrafish.…”

Section: Cpt-induced Downregulation Of Mll5 Is Conserved In Developinmentioning

confidence: 99%

Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

et al. 2011

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Mixed lineage leukemia 5 (MLL5) has been implicated in multiple aspects of cell physiology, such as hematopoiesis, cell cycle control and chromatin regulatory network. In this study, we present evidence that MLL5 is involved in the camptothecin (CPT)-induced p53 activation. CPT promoted the degradation of MLL5 protein in a time-and dose-dependent manner in actively replicating cells. The downregulation of MLL5 led to phosphorylation of p53 at Ser392, which was abrogated by exogenous overexpression of MLL5. In MLL5-knockdown cells, p53 protein was stabilized and bound to DNA with higher affinity, leading to activation of downstream genes. Co-immunoprecipitation showed that MLL5 preferentially interacted with the tetramerized form of p53, and knockdown of MLL5 promoted chromatin accumulation of p53 tetramers, suggesting that the association of MLL5 with p53 may prevent the p53 tetramers from binding to the chromatin target sites. The role of MLL5 in CPT-induced p53 activation was conserved in developing zebrafish, where CPT downregulated zebrafish Mll5 protein, and the microinjection of zebrafish mll5 mRNA substantially blocked the CPT-induced apoptosis. In summary, our study proposed MLL5 as a novel component in the regulation of p53 homeostasis and a new cellular determinant of CPT.

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Zebrafish as a Model Organism for the Identification and Characterization of Drugs and Genes Affecting p53 Signaling

Cited by 352 publications

References 21 publications

Hematopoietic defects in rps29 mutant zebrafish depend upon p53 activation

Hematopoietic defects in rps29 mutant zebrafish depend upon p53 activation

RhoA prevents apoptosis during zebrafish embryogenesis through activation of Mek/Erk pathway

Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

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