Interplay between the tumor suppressor p53 and TGFβ signaling shapes embryonic body axes in<i>Xenopus</i>

Takebayashi‐Suzuki, Kimiko; J, Funami; Tokumori, Daisuke; Saito, Akira; Watabe, Tetsuro; Miyazono, Kohei; Kanda, Akifumi; Suzuki, Atsushi

doi:10.1242/dev.00615

Cited by 68 publications

(59 citation statements)

References 63 publications

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“…It is also noteworthy that mutations in genes encoding interacting partners for Hipks, including p53, Cbp, Axin, and Ski, have been shown to cause exencephaly (35). Importantly, these have also been shown to be involved in the signaling cascades of Shh, Wnt, or BMPs (2,8,9,26,57,61). Therefore, in conclusion, it is hypothesized that coordination of the proliferation in the subdomains of neural tube and paraxial mesoderm is required for correct neural fold elevation and that Hipks could be involved in the coordination of the mitotic responses to various morphogenetic signals (66).…”

Section: Discussionmentioning

confidence: 99%

Overlapping Roles for Homeodomain-Interacting Protein Kinases Hipk1 and Hipk2 in the Mediation of Cell Growth in Response to Morphogenetic and Genotoxic Signals

Isono

Nemoto

et al. 2006

Molecular and Cellular Biology

100

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Homeodomain-interacting protein kinase 1 (Hipk1), 2, and 3 genes encode evolutionarily conserved nuclear serine/threonine kinases, which were originally identified as interacting with homeodomain-containing proteins. Hipks have been repeatedly identified as interactors for a vast range of functional proteins, including not only transcriptional regulators and chromatin modifiers but also cytoplasmic signal transducers, transmembrane proteins, and the E2 component of SUMO ligase. Gain-of-function experiments using cultured cells indicate growth regulatory roles for Hipks on receipt of morphogenetic and genotoxic signals. However, Hipk1 and Hipk2 singly deficient mice were grossly normal, and this is expected to be due to a functional redundancy between Hipk1 and Hipk2. Therefore, we addressed the physiological roles of Hipk family proteins by using Hipk1 Hipk2 double mutants. Hipk1 Hipk2 double homozygotes are progressively lost between 9.5 and 12.5 days postcoitus and frequently fail to close the anterior neuropore and exhibit exencephaly. This is most likely due to defective proliferation in the neural fold and underlying paraxial mesoderm, particularly in the ventral region, which may be attributed to decreased responsiveness to Sonic hedgehog signals. The present study indicated the overlapping roles for Hipk1 and Hipk2 in mediating cell proliferation and apoptosis in response to morphogenetic and genotoxic signals during mouse development.Homeodomain-interacting protein kinases (HIPKs) compose an evolutionarily conserved protein family in eukaryotes (37). Based on database screening, it appears that three closely related homologous genes encoding Hipks are conserved in vertebrates, including humans, mice, dogs, cows, and frogs (H. Koseki, unpublished). Mammalian HIPK1, HIPK2, and HIPK3 proteins were originally identified as nuclear protein kinases that function as corepressors for various homeodomain-containing transcriptional regulators, at least in part by forming a complex with Groucho and a histone deacetylase complex (7, 37). There is extensive structural similarity exhibited by the HIPKs with respect to their protein kinase domains, homeoprotein interaction domains, PEST sequences, and C-terminal regions enriched by tyrosine and histidine (YH domains). Although HIPK proteins are mainly found in the nucleus with a novel dot-like subnuclear distribution, which partially overlaps promyelocytic leukemia (PML) nuclear bodies, they are nevertheless also found in the cytoplasm (16,44,46). HIPKs have been consistently identified as interactors for a vast range of functional proteins, including not only transcriptional regulators and chromatin modifiers but also cytoplasmic signal transducers, transmembrane proteins, and the E2 component of SUMO ligase

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Section: Discussionmentioning

confidence: 99%

Overlapping Roles for Homeodomain-Interacting Protein Kinases Hipk1 and Hipk2 in the Mediation of Cell Growth in Response to Morphogenetic and Genotoxic Signals

Isono

Nemoto

et al. 2006

Molecular and Cellular Biology

100

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“…53 This is in contrast to p53-deficient Xenopus embryos, which display compromised cell differentiation during early stages of development. [54][55][56] Here, p53 is required for proper transforming growth factor beta (TGFb) signaling and mesoderm formation, consistent with a physical interaction of p53 with Smad proteins. 55,56 The reasons for the different requirements of p53 during early mammalian, fish and amphibian development are unclear, but might be due to the presence of other p53 family members (p63, p73) in mammals and zebrafish, whereas they appear to be absent during early stages of Xenopus development.…”

Section: Disruption Of Pold1 Leads To An Upregulation Of Genes Involvmentioning

confidence: 82%

p53 deficiency rescues apoptosis and differentiation of multiple cell types in zebrafish flathead mutants deficient for zygotic DNA polymerase δ1

et al. 2005

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Cell culture work has identified the tumor suppressor p53 as a component of the S-phase checkpoint control system, while in vivo studies of this role of p53 in whole-vertebrate systems were limited. Here, we describe zebrafish mutants in the DNA polymerase delta catalytic subunit 1, based on the positional cloning of the flathead (fla) gene. fla mutants display specific defects in late proliferative zones, such as eyes, brain and cartilaginous elements of the visceral head skeleton, where cells display compromised DNA replication, followed by apoptosis, and partial or complete loss of affected tissues. Antisense-mediated knockdown of p53 in fla mutants leads to a striking rescue of all phenotypic traits, including completion of replication, survival of cells, and normal differentiation and tissue formation. This indicates that under replicationcompromised conditions, the p53 branch of the S-phase checkpoint is responsible for eliminating stalled cells that, given more time, would have otherwise finished their normal developmental program.

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“…In our present study, the expression of puma and bax was upregulated following an increase in p53 protein stability caused by BMP-4 treatment. Smad1/5 could bind to p53 (Takebayashi-Suzuki et al, 2003), raising the possibilities that Smad1/5 signals cooperatively activate p53-dependent transcription through regulating post-translational modification of p53, such as phosphorylation or acetylation, or perturb the physical interaction between MDM2 and p53 thus protecting p53 from degradation. On the other hand, BMP-4 had a minor effect on the apoptosis of myeloma cells lacking p53, but inhibited their proliferation at relatively high doses (30 ng/ml or more) through upregulation of p21waf1 (data not shown) (Kawamura et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Execution of BMP-4-induced apoptosis by p53-dependent ER dysfunction in myeloma and B-cell hybridoma cells

et al. 2006

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Bone morphogenic protein (BMP)-4 inhibits proliferation and induces the apoptosis of myeloma cells. However, little is known about the molecular mechanisms of how BMP-4 executes this apoptosis. In this report, we investigated the roles of p53 and the endoplasmic reticulum (ER) in BMP-4-induced apoptosis of mouse hybridoma HS-72 cells. We found that 3 ng/ml of BMP-4 is sufficient to induce the expression of proapoptotic proteins, puma and bax, in a p53-dependent mechanism, and facilitate Ca 2 þ release from the ER to the cytosol, resulting in the activation of caspase-12 and ER dysfunction. Similarly to HS-72 cells, multiple myeloma cells with wild-type p53 genes show much higher sensitivity to BMP-4-induced apoptosis than cells without wild-type p53 genes, suggesting that wild-type p53 status is required for dysfunction of the ER during BMP-4-induced apoptosis in ER-enriched cells, such as hybridoma and myeloma cells. These findings demonstrate that the presence of wild-type p53 genes and enrichment of the ER determines the sensitivity to effective apoptosis by BMP-4, and suggest that ER stress-inducing agents would be valuable in the treatment of multiple myeloma.

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Interplay between the tumor suppressor p53 and TGFβ signaling shapes embryonic body axes inXenopus

Cited by 68 publications

References 63 publications

Overlapping Roles for Homeodomain-Interacting Protein Kinases Hipk1 and Hipk2 in the Mediation of Cell Growth in Response to Morphogenetic and Genotoxic Signals

Overlapping Roles for Homeodomain-Interacting Protein Kinases Hipk1 and Hipk2 in the Mediation of Cell Growth in Response to Morphogenetic and Genotoxic Signals

p53 deficiency rescues apoptosis and differentiation of multiple cell types in zebrafish flathead mutants deficient for zygotic DNA polymerase δ1

Execution of BMP-4-induced apoptosis by p53-dependent ER dysfunction in myeloma and B-cell hybridoma cells

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