HIPK1 interacts with c-Myb and modulates its activity through phosphorylation

Matre, Vilborg; Nordgård, Oddmund; Alm-Kristiansen, Anne Hege; Ledsaak, Marit; Gabrielsen, Odd S.

doi:10.1016/j.bbrc.2009.07.139

Cited by 18 publications

(13 citation statements)

References 30 publications

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“…The maintenance of high levels of c-Myb, or its exogenous overexpression, suppresses normal differentiation and can promote leukemic transformation. 2,3 As expected, due to the importance of adequate levels of c-Myb during the different stages of hematopoiesis, its expression and activity are finely tuned by protein-protein interactions, [12][13][14][15][16][17] posttranslational modifications, 14,[18][19][20] and, as has been recently shown, miRNAmediated down-regulation. 21,22 The identification of genes targeted by c-Myb is essential for our understanding of the wide action of this transcription factor during development.…”

Section: Introductionmentioning

confidence: 72%

Identification of c-Myb Target Genes in K562 Cells Reveals a Role for c-Myb as a Master Regulator

et al. 2011

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The c-Myb transcription factor is an important regulator of hematopoietic cell development. c-Myb is expressed in immature hematopoietic cells and plays a direct role in lineage fate selection, cell cycle progression, and differentiation of myeloid as well as B- and T-lymphoid progenitor cells. As a DNA-binding transcription factor, c-Myb regulates specific gene programs through activation of target genes. Still, our understanding of these programs is incomplete. Here, we report a set of novel c-Myb target genes, identified using a combined approach: specific c-Myb knockdown by 2 different siRNAs and subsequent global expression profiling, combined with the confirmation of direct binding of c-Myb to the target promoters by ChIP assays. The combination of these 2 approaches, as well as additional validation such as cloning and testing the promoters in reporter assays, confirmed that MYADM, LMO2, GATA2, STAT5A, and IKZF1 are target genes of c-Myb. Additional studies, using chromosome conformation capture, demonstrated that c-Myb target genes may directly interact with each other, indicating that these genes may be coordinately regulated. Of the 5 novel target genes identified, 3 are transcription factors, and one is a transcriptional co-regulator, supporting a role of c-Myb as a master regulator controlling the expression of other transcriptional regulators in the hematopoietic system.

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Section: Introductionmentioning

confidence: 72%

Identification of c-Myb Target Genes in K562 Cells Reveals a Role for c-Myb as a Master Regulator

et al. 2011

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“…For example, Hipk1 and Hipk2 have functionally redundant roles in mediating cell proliferation and apoptosis during development (Inoue et al, 2010;Isono et al, 2006). Hipk1 interacts with transcription factor c-Myb (Matre et al, 2009), while Hipk2 phosphorylates transcriptional co-repressor Groucho , suggesting their distinct roles in transcription regulation. Therefore, it would be interesting to elucidate whether Drosophila Hipk executes the functions of all the mammalian counterparts, although Drosophila Hipk shares most homology with Hipk2.…”

Section: Research Articlementioning

confidence: 99%

Drosophila Smt3 negatively regulates JNK signaling through sequestering Hipk in the nucleus

Huang

Chen

et al. 2011

Development

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SUMMARYPost-translational modification by the small ubiquitin-related modifier (SUMO) is important for a variety of cellular and developmental processes. However, the precise mechanism(s) that connects sumoylation to specific developmental signaling pathways remains relatively less clear. Here, we show that Smt3 knockdown in Drosophila wing discs causes phenotypes resembling JNK gain of function, including ectopic apoptosis and apoptosis-induced compensatory growth. Smt3 depletion leads to an increased expression of JNK target genes Mmp1 and puckered. We show that, although knockdown of the homeodomaininteracting protein kinase (Hipk) suppresses Smt3 depletion-induced activation of JNK, Hipk overexpression synergistically enhances this type of JNK activation. We further demonstrate that Hipk is sumolylated in vivo, and its nuclear localization is dependent on the sumoylation pathway. Our results thus establish a mechanistic connection between the sumoylation pathway and the JNK pathway through the action of Hipk. We propose that the sumoylation-controlled balance between cytoplasmic and nuclear Hipk plays a crucial role in regulating JNK signaling.

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“…In addition, c-Myb is also modulated by post-translational modifications as well as by protein-protein interactions. c-Myb is phosphorylated at several sites by different kinases [14,20-23], sumoylated at two lysine residues in the C-terminal regulatory domain [24-26] and acetylated by the co-activator CBP/p300 [27,28]. Moreover, different factors have been reported to interact with c-Myb regulating its activity; besides FLASH [6], we have also earlier identified another co-activator of c-Myb, the chromatin remodelling factor Mi-2α, shown to regulate endogenous c-Myb target genes [29].…”

Section: Introductionmentioning

confidence: 99%

PIAS1 interacts with FLASH and enhances its co-activation of c-Myb

et al. 2011

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BackgroundFLASH is a huge nuclear protein involved in various cellular functions such as apoptosis signalling, NF-κB activation, S-phase regulation, processing of histone pre-mRNAs, and co-regulation of transcription. Recently, we identified FLASH as a co-activator of the transcription factor c-Myb and found FLASH to be tightly associated with active transcription foci. As a huge multifunctional protein, FLASH is expected to have many interaction partners, some which may shed light on its function as a transcriptional regulator.ResultsTo find additional FLASH-associated proteins, we performed a yeast two-hybrid (Y2H) screening with FLASH as bait and identified the SUMO E3 ligase PIAS1 as an interaction partner. The association appears to involve two distinct interaction surfaces in FLASH. We verified the interaction by Y2H-mating, GST pulldowns, co-IP and ChIP. FLASH and PIAS1 were found to co-localize in nuclear speckles. Functional assays revealed that PIAS1 enhances the intrinsic transcriptional activity of FLASH in a RING finger-dependent manner. Furthermore, PIAS1 also augments the specific activity of c-Myb, and cooperates with FLASH to further co-activate c-Myb. The three proteins, FLASH, PIAS1, and c-Myb, are all co-localized with active RNA polymerase II foci, resembling transcription factories.ConclusionsWe conclude that PIAS1 is a common partner for two cancer-related nuclear factors, c-Myb and FLASH. Our results point to a functional cooperation between FLASH and PIAS1 in the enhancement of c-Myb activity in active nuclear foci.

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HIPK1 interacts with c-Myb and modulates its activity through phosphorylation

Cited by 18 publications

References 30 publications

Identification of c-Myb Target Genes in K562 Cells Reveals a Role for c-Myb as a Master Regulator

Identification of c-Myb Target Genes in K562 Cells Reveals a Role for c-Myb as a Master Regulator

Drosophila Smt3 negatively regulates JNK signaling through sequestering Hipk in the nucleus

PIAS1 interacts with FLASH and enhances its co-activation of c-Myb

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