HoxA10 Represses Gene Transcription in Undifferentiated Myeloid Cells by Interaction with Histone Deacetylase 2

Lu, Yu Feng; Goldenberg, Inna; Bei, Ling; Andrejic, Jelena; Eklund, Elizabeth A.

doi:10.1074/jbc.m305885200

Cited by 37 publications

(68 citation statements)

References 36 publications

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“…We found that CYBB and NCF2 transcription is repressed in undifferentiated myeloid cells by interaction of HoxA10, Pbx1, and HDAC2 with homologous cis-elements in these genes (24).…”

mentioning

confidence: 76%

“…Consistent with this, transcription is regulated by homologous CYBB and NCF2 ciselements that interact with a common set of transcription factors. In this study, we investigated the homologous negative cis-elements that are repressed by HoxA10 (20,21,24). Additionally, homologous positive cis-elements in the proximal promoters of these genes are activated by a multiprotein complex that includes PU.1, interferon regulatory factor-1, interferon consensus sequence-binding protein (ICSBP), and the cAMP-responsive element-binding protein-binding protein (13,45,46,51).…”

Section: Discussionmentioning

confidence: 99%

“…HDAC2 (20,24,28). In IFN-␥-differentiated control transfectants, decreased binding of the low mobility complex was accompanied by increased binding of a higher mobility complex.…”

Section: Expression Of a Leukemia-associated Activating Shp2 Ptp Mutamentioning

confidence: 99%

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Activation of SHP2 Protein-tyrosine Phosphatase Increases HoxA10-induced Repression of the Genes Encoding gp91PHOX and p67PHOX

Lindsey

Huang

Wang

et al. 2007

Journal of Biological Chemistry

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The CYBB and NCF2 genes encode the phagocyte oxidase proteins gp91 PHOX and p67 PHOX , respectively. These genes are transcribed after the promyelocyte stage of differentiation, and transcription continues until cell death. In undifferentiated myeloid cells, homologous cis-elements in the CYBB and NCF2 genes are repressed by the homeodomain transcription factor HoxA10. During cytokine-induced myelopoiesis, tyrosine phosphorylation of HoxA10 decreases binding affinity for the CYBB and NCF2 ciselements. This abrogates HoxA10-induced transcriptional repression as differentiation proceeds. Therefore, mechanisms involved in differentiation stage-specific HoxA10 tyrosine phosphorylation are of interest because HoxA10 phosphorylation modulates myeloid-specific gene transcription. In this study, we found that HoxA10 is a substrate for SHP2 protein-tyrosine phosphatase in undifferentiated myeloid cells. In contrast, HoxA10 is a substrate for a constitutively active mutant form of SHP2 in both undifferentiated and differentiating myeloid cells. Expression of such SHP2 mutants results in persistent HoxA10 repression of CYBB and NCF2 transcription during myelopoiesis. Both HoxA10 overexpression and activating SHP2 mutations have been described in human myeloid malignancies. Therefore, our results suggest that these mutations could cooperate, leading to decreased myeloidspecific gene transcription and functional differentiation block in myeloid cells with both defects.

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“…We found that CYBB and NCF2 transcription is repressed in undifferentiated myeloid cells by interaction of HoxA10, Pbx1, and HDAC2 with homologous cis-elements in these genes (24).…”

mentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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Activation of SHP2 Protein-tyrosine Phosphatase Increases HoxA10-induced Repression of the Genes Encoding gp91PHOX and p67PHOX

Lindsey

Huang

Wang

et al. 2007

Journal of Biological Chemistry

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“…These sequences were subcloned into the pSR␣ vector for expression in mammalian cells. HoxA10 cDNAs with mutation of the Pbx1 interaction domain were generated by PCRbased site-directed mutagenesis, by a previously described technique (19). The wild type HoxA10 was mutated to change amino acid 312 from asparagine to alanine and amino acid 313 from tryptophan to threonine (N312A/W323T HoxA10).…”

Section: Plasmids and Pcr Mutagenesismentioning

confidence: 99%

“…However, we found that HoxA10-repression of CYBB and NCF2 transcription was Pbx-independent and involved direct interaction of HoxA10 with the corepressor histone deacetylase 2 (HDAC2) (15,19). This interaction required a unique HoxA10 domain, not conserved in other Abd HoxA proteins (19). As differentiation proceeds, HoxA10 binding to the CYBB and NCF2 genes decreases, relieving repression (14,15).…”

mentioning

confidence: 91%

Identification of a HoxA10 Activation Domain Necessary for Transcription of the Gene Encoding β3 Integrin during Myeloid Differentiation

Bei

Bellis

et al. 2007

Journal of Biological Chemistry

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Transcription of the ITGB3 gene, which encodes ␤3 integrin, increases during myeloid differentiation. ␣v␤3 integrin mediates adhesion to fibronectin or vitronectin and regulates various aspects of the inflammatory response in mature phagocytes. In these studies, we found that the homeodomain transcription factor HoxA10 interacted with a specific ITGB3 cis element and activated transcription of this gene during myeloid differentiation. We also found that increased fibronectin adhesion in differentiating myeloid cells was dependent upon this HoxA10-induced increase in ␤3 integrin expression. We determined that activation of ITGB3 transcription required a HoxA10 domain that was not identical to the "hexapeptide" that mediates interaction of Hox and Pbx proteins. This activation domain was also not identical to a previously identified HoxA10 repression domain that mediates interaction with transcriptional co-repressors. Instead, this HoxA10 activation domain had homology to "PQ" protein-protein interaction domains that have been described previously in other transcription factors. Consistent with this, we found that the HoxA10 PQ-like domain recruited the CREB-binding protein (CBP) to the ITGB3 promoter. This was associated with an increase in local histone acetylation in vivo. In immature myeloid cells, we previously determined that HoxA10 repressed transcription of the CYBB and NCF2 genes, which encode the phagocyte oxidase proteins gp91 PHOX and p67 PHOX , respectively. Therefore, our studies indicated that HoxA10 either activates or represses gene transcription at various points during myelopoiesis. Our studies also suggested that HoxA10 is a bifunctional protein that is involved in dynamic regulation of multiple aspects of phagocyte phenotype and function.

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“Self‐regulation,” a new facet of Hox genes' function

Sheth

Bastida

Kmita

et al. 2013

Developmental Dynamics

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Background: Precise temporal and spatial expression of the clustered Hox genes is essential for patterning the developing embryo. Temporal activation of Hox genes was shown to be cluster-autonomous. However, gene clustering appears dispensable for spatial colinear expression. Generally, a set of Hox genes expressed in a group of cells instructs these cells about their fate such that the differential expression of Hox genes results in morphological diversity. The spatial colinearity is considered to rely both on local and long-range cis regulation. Results: Here, we report on the global deregulation of HoxA and HoxD expression patterns upon inactivation of a subset of HOXA and HOXD proteins. Conclusions: Our data suggest the existence of a "self-regulation" mechanism, a process by which HOX proteins establish and/or maintain the spatial domains of the Hox gene family and we propose that the functionally dominant HOX proteins could contribute to generating the spatial parameters of Hox expression in a given tissue, i.e., HOX controlling the establishment of the ultimate HOX code. Developmental Dynamics 00:000-000,

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HoxA10 Represses Gene Transcription in Undifferentiated Myeloid Cells by Interaction with Histone Deacetylase 2

Abstract: The homeodomain proteins, HoxA10 and Pbx1a, interact with negative cis elements to repress gene transcription in undifferentiated myeloid cells. The CYBB and NCF2 genes, which encode the gp91 PHOX

Cited by 37 publications

References 36 publications

Activation of SHP2 Protein-tyrosine Phosphatase Increases HoxA10-induced Repression of the Genes Encoding gp91PHOX and p67PHOX

Activation of SHP2 Protein-tyrosine Phosphatase Increases HoxA10-induced Repression of the Genes Encoding gp91PHOX and p67PHOX

Identification of a HoxA10 Activation Domain Necessary for Transcription of the Gene Encoding β3 Integrin during Myeloid Differentiation

“Self‐regulation,” a new facet of Hox genes' function

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