Runt-related Transcription Factor 1 (RUNX1) Stimulates Tumor Suppressor p53 Protein in Response to DNA Damage through Complex Formation and Acetylation

Wu, Dan; Ozaki, Toshinori; Yoshihara, Yukari; Kubo, Natsumi; Nakagawara, Akira

doi:10.1074/jbc.m112.402594

Cited by 52 publications

(38 citation statements)

References 58 publications

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“…According to our recent results [108], RUNX1 together with p53 accumulated in human osteosarcoma-derived U2OS cell nucleus following ADR exposure, formed a stable complex, and was recruited onto p53-activated promoters including p21 WAF1 and BAX , suggesting that RUNX1 might affect the transcriptional activity of p53. Knockdown of RUNX1 resulted in a significant reduction of ADR-mediated apoptotic cell death in association with a remarkable downregulation of p53-responsive gene expression.…”

Section: Runx1 Acts As a Positive Regulator For P53-dependent Apopmentioning

confidence: 87%

RUNX Family Participates in the Regulation of p53-Dependent DNA Damage Response

Ozaki

Nakagawara

Nagase

2013

International Journal of Genomics

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A proper DNA damage response (DDR), which monitors and maintains the genomic integrity, has been considered to be a critical barrier against genetic alterations to prevent tumor initiation and progression. The representative tumor suppressor p53 plays an important role in the regulation of DNA damage response. When cells receive DNA damage, p53 is quickly activated and induces cell cycle arrest and/or apoptotic cell death through transactivating its target genes implicated in the promotion of cell cycle arrest and/or apoptotic cell death such as p21WAF1, BAX, and PUMA. Accumulating evidence strongly suggests that DNA damage-mediated activation as well as induction of p53 is regulated by posttranslational modifications and also by protein-protein interaction. Loss of p53 activity confers growth advantage and ensures survival in cancer cells by inhibiting apoptotic response required for tumor suppression. RUNX family, which is composed of RUNX1, RUNX2, and RUNX3, is a sequence-specific transcription factor and is closely involved in a variety of cellular processes including development, differentiation, and/or tumorigenesis. In this review, we describe a background of p53 and a functional collaboration between p53 and RUNX family in response to DNA damage.

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Section: Runx1 Acts As a Positive Regulator For P53-dependent Apopmentioning

confidence: 87%

RUNX Family Participates in the Regulation of p53-Dependent DNA Damage Response

Ozaki

Nakagawara

Nagase

2013

International Journal of Genomics

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“…Indeed, it cooperates with p53 after DNA damage and is recruited onto p53 target gene promoters. 45 In addition, a decreased expression of the direct RUNX1 target GADD45A, encoding for a sensor of DNA stress, was observed in bone marrow cells from MDS/AML patients harboring a RUNX1 mutation in the C-terminal domain. 19 GADD45A was shown to be activated synergistically by RUNX1 and p53.…”

Section: Discussionmentioning

confidence: 99%

Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia

Antony-Debré

Manchev

Balayn

et al. 2015

Blood

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Key Points• A half loss of RUNX1 activity leads to defects in primitive erythropoiesis, megakaryopoiesis, and proplatelet formation.• An almost complete loss of RUNX1 activity leads to the amplification of the granulomonocytic compartment with increased genomic instability.To explore how RUNX1 mutations predispose to leukemia, we generated induced pluripotent stem cells (iPSCs) from 2 pedigrees with germline RUNX1 mutations. The first, carrying a missense R174Q mutation, which acts as a dominant-negative mutant, is associated with thrombocytopenia and leukemia, and the second, carrying a monoallelic gene deletion inducing a haploinsufficiency, presents only as thrombocytopenia. Hematopoietic differentiation of these iPSC clones demonstrated profound defects in erythropoiesis and megakaryopoiesis and deregulated expression of RUNX1 targets. iPSC clones from patients with the R174Q mutation specifically generated an increased amount of granulomonocytes, a phenotype reproduced by an 80% RUNX1 knockdown in the H9 human embryonic stem cell line, and a genomic instability. This phenotype, found only with a lower dosage of RUNX1, may account for development of leukemia in patients. Altogether, RUNX1 dosage could explain the differential phenotype according to RUNX1 mutations, with a haploinsufficiency leading to thrombocytopenia alone in a majority of cases whereas a more complete gene deletion predisposes to leukemia. (Blood. 2015; 125(6):930-940)

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“…50), WTX 37 and RUNX1 (ref. 51). Interestingly, the pro-p53 effects are often independent of the canonical activities of these proteins.…”

Section: Discussionmentioning

confidence: 99%

ArhGAP30 promotes p53 acetylation and function in colorectal cancer

Wang

Qian

et al. 2014

Nat Commun

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Covalent modification adding acetyl groups to the C terminus of the p53 protein has been suggested to be required for its functional activation as a tumour suppressor. However, it remains largely unknown how p53 acetylation is deregulated in colorectal cancer (CRC), which is the third most commonly diagnosed cancer worldwide. Here we show that ArhGAP30, a Rho GTPase-activating protein, is a pivotal regulator for p53 acetylation and functional activation in CRC. ArhGAP30 binds to p53 C-terminal domain and P300, facilitating P300-mediated acetylation of p53 at lysine 382. ArhGAP30 expression is required for p53 activation upon DNA damage stress, and the level of ArhGAP30 correlates with p53 acetylation and functional activation in CRC tissues. Moreover, low level of ArhGAP30 expression associates with poor survival of CRC patients. In summary, ArhGAP30 is required for p53 acetylation and functional activation in CRC, and the expression of ArhGAP30 is a potential prognostic marker for CRC.

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Runt-related Transcription Factor 1 (RUNX1) Stimulates Tumor Suppressor p53 Protein in Response to DNA Damage through Complex Formation and Acetylation

Cited by 52 publications

References 58 publications

RUNX Family Participates in the Regulation of p53-Dependent DNA Damage Response

RUNX Family Participates in the Regulation of p53-Dependent DNA Damage Response

Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia

ArhGAP30 promotes p53 acetylation and function in colorectal cancer

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