Monocytic Leukemia Zinc Finger (MOZ) Interacts with p53 to Induce p21 Expression and Cell-cycle Arrest

Rokudai, Susumu; Aikawa, Yuri; Tagata, Yusuke; Tsuchida, Nobuo; Taya, Yoichi; Kitabayashi, Issay

doi:10.1074/jbc.m805101200

Cited by 75 publications

(69 citation statements)

References 53 publications

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“…Indeed, it was recently shown that interactions between AML1/RUNX1 and MLL provide epigenetic regulation of gene expression in normal hematopoiesis and in leukemia (Huang G, personal communication) (Huang et al, 2008). MOZ is also associated with other transcription factors such as RUNX2, C/EBPa, C/EBPb, c-Jun, NF-kB, Nrf2/MafK and p53 (Pelletier et al, 2002;Ohta et al, 2005Ohta et al, , 2007Katsumoto et al, 2006;Chan et al, 2007;Rokudai et al, 2009). In addition, it was reported that MLL is a protein partner of p53 and HCF-1 in a cell cycle-dependent manner (Tyagi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

et al. 2010

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MOZ and MLL, encoding a histone acetyltransferase (HAT) and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. In MOZ (MOnocytic leukemia Zinc-finger protein)/CBP-or mixed lineage leukemia (MLL)-rearranged leukemias, abnormal levels of HOX transcription factors have been found to be critical for leukemogenesis. We show that MOZ and MLL cooperate to regulate these key genes in human cord blood CD34 þ cells. These chromatinmodifying enzymes interact, colocalize and functionally cooperate, and both are recruited to multiple HOX promoters. We also found that WDR5, an adaptor protein essential for lysine 4 trimethylation of histone H3 (H3K4me3) by MLL, colocalizes and interacts with MOZ. We detected the binding of the HAT MOZ to H3K4me3, thus linking histone methylation to acetylation. In CD34 þ cells, depletion of MLL causes release of MOZ from HOX promoters, which is correlated to defective histone activation marks, leading to repression of HOX gene expression and alteration of commitment of CD34 þ cells into myeloid progenitors. Thus, our results unveil the role of the interaction between MOZ and MLL in CD34 þ cells in which both proteins have a critical role in hematopoietic cell-fate decision, suggesting a new molecular mechanism by which MOZ or MLL deregulation leads to leukemogenesis.

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Section: Discussionmentioning

confidence: 99%

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

et al. 2010

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“…81 The MOZ-CBP (CREB-binding protein) FP of t(8;16) AML also decreases p53 acetylation, thus mitigating p53 transcriptional activity, which probably yields the downregulation of several p53-related microRNAs, such as miR-34a. 82,83 In CML-Ph 11 blast-phase leukemia wtp53 inactivation is mediated by p53 deacetylation via SIRT1 (HDAC-III) upregulation and by MDM2 upregulation via BCR-ABL-induced La-antigen overexpression. 68,84 Another inactivating mechanism is operated by MOZ-TIF2 of inv(8) AML, which causes CBP mislocalization from PML bodies, depletion of its cellular levels, and reduction of CBPdependent p53 transcriptional activity.…”

Section: Aml With Chromosomal Translocationsmentioning

confidence: 99%

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

Prokocimer

Molchadsky

Rotter

2017

Blood

138

119

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The heterogeneous nature of acute myeloid leukemia (AML) and its poor prognosis necessitate therapeutic improvement. Current advances in AML research yield important insights regarding AML genetic, epigenetic, evolutional, and clinical diversity, all in which dysfunctional p53 plays a key role. As p53 is central to hematopoietic stem cell functions, its aberrations affect AML evolution, biology, and therapy response and usually predict poor prognosis. While in human solid tumors TP53 is mutated in more than half of cases, TP53 mutations occur in less than one tenth of de novo AML cases. Nevertheless, wild-type (wt) p53 dysfunction due to nonmutational p53 abnormalities appears to be rather frequent in various AML entities, bearing, presumably, a greater impact than is currently appreciated. Hereby, we advocate assessment of adult AML with respect to coexisting p53 alterations. Accordingly, we focus not only on the effects of mutant p53 oncogenic gain of function but also on the mechanisms underlying nonmutational wtp53 inactivation, which might be of therapeutic relevance. Patient-specific TP53 genotyping with functional evaluation of p53 protein may contribute significantly to the precise assessment of p53 status in AML, thus leading to the tailoring of a rationalized and precision p53-based therapy. The resolution of the mechanisms underlying p53 dysfunction will better address the p53-targeted therapies that are currently considered for AML. Additionally, a suggested novel algorithm for p53-based diagnostic workup in AML is presented, aiming at facilitating the p53-based therapeutic choices. (Blood. 2017; 130(6):699-712)

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“…Associated factors present within these complexes may also contribute to the acetylation specificity of these nonhistone substrates. A few targets have been identified for the MYST acetyltransferase family (for a detailed review, see (Sapountzi and Cote 2011), including the p53 tumor suppressor protein, which can be acetylated on different lysine residues by these enzymes (Sykes et al 2006;Tang et al 2006Tang et al , 2008Li et al 2009;Rokudai et al 2009Rokudai et al , 2013. The MOF MYST acetyltransferase has been shown to be part of two separate complexes, MOF-MSL and MOF-MSL1v1 (Smith et al 2005;Li et al 2009).…”

Section: Conflicting Reports On Specificity Of Histone Modifiersmentioning

confidence: 99%

Histone target selection within chromatin: an exemplary case of teamwork

2014

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Histone modifiers like acetyltransferases, methyltransferases, and demethylases are critical regulators of most DNA-based nuclear processes, de facto controlling cell cycle progression and cell fate. These enzymes perform very precise post-translational modifications on specific histone residues, which in turn are recognized by different effector modules/proteins. We now have a better understanding of how these enzymes exhibit such specificity. As they often reside in multisubunit complexes, they use associated factors to target their substrates within chromatin structure and select specific histone mark-bearing nucleosomes. In this review, we cover the current understanding of how histone modifiers select their histone targets. We also explain how different experimental approaches can lead to conflicting results about the histone specificity and function of these enzymes.

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Monocytic Leukemia Zinc Finger (MOZ) Interacts with p53 to Induce p21 Expression and Cell-cycle Arrest

Cited by 75 publications

References 53 publications

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

Histone target selection within chromatin: an exemplary case of teamwork

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