Regulation of Gli1 Transcriptional Activity in the Nucleus by Dyrk1

Mao, Junhao; Maye, Peter; Kogerman, Priit; Tejedor, Francisco Javier Tejedor; Toftgárd, Rune; Xie, Wei; Wu, Guanqing; Wu, Dianqing

doi:10.1074/jbc.m206743200

Cited by 177 publications

(171 citation statements)

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“…Mirk, similar to Dyrk1A, functions as a transcriptional activator (8,22,23). We have shown in the current study that Mirk also functions by mediating protein degradation.…”

Section: Discussionsupporting

confidence: 60%

Mirk/dyrk1B Kinase Destabilizes Cyclin D1 by Phosphorylation at Threonine 288

Zou

Ewton

Deng

et al. 2004

Journal of Biological Chemistry

109

122

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The phosphorylation of cyclin D1 at threonine 286 by glycogen synthase kinase 3␤ (GSK3␤) has been shown to be required for the ubiquitination and nuclear export of cyclin D1 and its subsequent degradation in the proteasome. The mutation of the nearby residue, threonine 288, to nonphosphorylatable alanine has also been shown to reduce the ubiquitination of cyclin D1, suggesting that phosphorylation at threonine 288 may also lead to degradation of cyclin D1. We now demonstrate that the G 0 /G 1 -active arginine-directed protein kinase Mirk/dyrk1B binds to cyclin D1 and phosphorylates cyclin D1 at threonine 288 in vivo and that the cyclin D1-T288A construct is more stable than wild-type cyclin Cell cycle progression in eukaryotic cells is mediated by cyclin-dependent kinases (CDKs). 1 The D-type cyclins, D1, D2, and D3, increase in nuclear abundance in G 1 in response to mitogens, facilitate the import of CDK4 into the nucleus (1), and assemble combinatorially with CDK4 or CDK6 into complexes that phosphorylate the retinoblastoma protein, releasing factors needed for the progression into S phase. Cyclin D1 is translocated into the cytoplasm during S phase where it is destroyed by the proteasome following phosphorylation at threonine 286 by GSK3␤ (2, 3). Mutant cyclin D1-T286A, which cannot be phosphorylated by GSK3␤, is stabilized in the nucleus and is capable of transforming murine fibroblasts, whereas overexpression of wild-type cyclin D1 cannot act alone to transform such cells (4). A cyclin D1 isoform derived by alternative splicing was shown to lack threonine 286, enabling this cyclin D1 isoform to remain nuclear throughout the cell cycle, remain highly expressed, and function to facilitate transformation of NIH3T3 cells (5). This cyclin D1 splice variant was also found in tumor-derived cells and primary human esophageal tumors (5). Overexpression of cyclin D1 occurs in several cancers including breast, pancreatic, and esophageal (6), suggesting that either increased transcription, transcription of stable splice variants, or dysregulation of cyclin D1 turnover may frequently occur in cancer.In this study, we have studied the interaction of the ubiquitously expressed protein kinase Mirk/dyrk1B with cyclin D1. Mirk/dyrk1B is an arginine-directed serine/threonine kinase (7), which functions as a transcriptional co-activator and is activated through the stress-activated mitogen-activated protein kinase kinase MKK3 (8). We have shown recently that Mirk stabilizes the CDK inhibitor p27kip1 in the G 0 phase of the cell cycle in NIH3T3 fibroblasts, whereas depletion of Mirk by RNA interference increases cell cycling as measured by increased PCNA expression (9). Mirk expression is decreased by mitogen activation of the MEK-ERK pathway during G 1 (10), restricting Mirk function primarily to G 0 and early G 1 . We now confirm that transient overexpression of Mirk in nontransformed Mv1Lu lung epithelial cells increases the length of G 0 /G 1 by FACS analysis and that Mirk targets the G 1 cell cycle regulator, cyclin D1, t...

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“…Mirk, similar to Dyrk1A, functions as a transcriptional activator (8,22,23). We have shown in the current study that Mirk also functions by mediating protein degradation.…”

Section: Discussionsupporting

confidence: 60%

Mirk/dyrk1B Kinase Destabilizes Cyclin D1 by Phosphorylation at Threonine 288

Zou

Ewton

Deng

et al. 2004

Journal of Biological Chemistry

109

122

View full text Add to dashboard Cite

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“…However, DYRK1A had no effect on ERK activity in HeLa and Cos-7 cells ( Figure 2B; our unpublished data). Previously reported data also showed no effect of DYRK1A on ERK activity in NIH 3T3 cells (Mao et al, 2002). These findings indicate that the effect of DYRK1A on the Ras/MAP kinase pathway is cell line specific (discussed in Figure 6D).…”

supporting

confidence: 72%

“…which indicates that DYRK1A associates specifically with B-Raf. The inability of DYRK1A to activate the Ras/MAP kinase pathway in HeLa ( Figure 2B), Cos-7 (our unpublished data) and NIH 3T3 cells (Mao et al, 2002) could be explained by the fact that DYRK1A does not interact with Raf1, whereas it does interact with the neuron-specific Raf isoform B-Raf. Indeed, HeLa, Cos-7, and NIH 3T3 cells predominantly express Raf1 but not B-Raf, whereas PC12 cells express high levels of both Raf isoforms (Vossler et al, 1997).…”

mentioning

confidence: 78%

“…Additionally, DYRK1A phosphorylates several substrates in vitro, This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E04 -12-1085) on May 25, 2005. including the signal transducer and activator of transcription 3 (Matsuo et al, 2001), the eukaryotic initiation factor 2B⑀ (Woods et al, 2001a), the microtubule-associated protein Tau (Woods et al, 2001a), the transcription factor of the Forkhead family (FHKR) (Woods et al, 2001b), dynamin (Chen-Hwang et al, 2002), glycogen synthase (Skurat and Dietrich, 2004), cyclin L2 (De Graaf et al, 2004), and 14-3-3 (Kim et al, 2004), indicating that DYRK1A may participate in several biochemicals pathways (reviewed in Galceran et al, 2003;Hämmerle et al, 2003b). In vivo, DYRK1A interacts with and activates Gli-1-dependent gene transcription (Mao et al, 2002). Moreover, DYRK1A increases FKHR-dependent glucose-6-phosphatase gene expression in hepatoma cells (von Groote-Bidlingmaier et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…In vivo, DYRK1A interacts with and activates Gli-1-dependent gene transcription (Mao et al, 2002). Moreover, DYRK1A increases FKHR-dependent glucose-6-phosphatase gene expression in hepatoma cells (von Groote-Bidlingmaier et al, 2003).…”

mentioning

confidence: 99%

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DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1

Kelly

Rahmani

2005

MBoC

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Dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) is the human homologue of the Drosophila mnb (minibrain) gene. In Drosophila, mnb is involved in postembryonic neurogenesis. In human, DYRK1A maps within the Down syndrome critical region of chromosome 21 and is overexpressed in Down syndrome embryonic brain. Despite its potential involvement in the neurobiological alterations observed in Down syndrome patients, the biological functions of the serine/threonine kinase DYRK1A have not been identified yet. Here, we report that DYRK1A overexpression potentiates nerve growth factor (NGF)-mediated PC12 neuronal differentiation by up-regulating the Ras/MAP kinase signaling pathway independently of its kinase activity. Furthermore, we show that DYRK1A prolongs the kinetics of ERK activation by interacting with Ras, B-Raf, and MEK1 to facilitate the formation of a Ras/B-Raf/MEK1 multiprotein complex. These data indicate that DYRK1A may play a critical role in Ras-dependent transducing signals that are required for promoting or maintaining neuronal differentiation and suggest that overexpression of DYRK1A may contribute to the neurological abnormalities observed in Down syndrome patients. INTRODUCTIONMinibrain (mnb)/dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) gene is a member of a growing family of protein kinases called DYRK. In Drosophila, mnb seems to play an essential role during postembryonic neurogenesis. Mutant flies are characterized by a marked reduction in size of the adult optic lobes and the central brain hemispheres. This is caused by the abnormal spacing of neuroblasts and a reduction in the production of neuronal progeny (Tejedor et al., 1995). At least seven closely related homologous mammalian kinases in the DYRK family have since been isolated (Guimera et al., 1996(Guimera et al., , 1999Shindoh et al., 1996;Song et al., 1996Song et al., , 1997Raich et al., 2003). The DYRK family possesses serine and threonine phosphorylation activity as well as autophosphorylation activity on tyrosine residues (Kentrup et al., 1996;Becker et al., 1998;Becker and Joost, 1999;Himpel et al., 2000). Their kinase activity is dependent on the YXY motif in the activation loop of the catalytic domain, which is located at the same position as the characteristic TXY motif of the mitogen-activated protein kinases (MAPKs), suggesting an activation mechanism similar to that of the MAPK (Himpel et al., 2000). Closely related enzymes in lower eukaryotes also have been isolated, including Yak1p in Saccharomyces cerevisiae (Garrett and Broach, 1989), Pom1p in Schizosaccharomyces pombe (Bahler and Pringle, 1998), and YakA in Dictyostelium discoideum (Van Es et al., 2001). Although not much is known about their cellular functions, they all seem to be involved in the regulation of the cell growth and/or development.In the DYRK family, DYRK1A has been the best characterized to date. The human Dyrk1A gene maps to the 21q22.2 region of chromosome 21, in the Down syndrome critical region (Rah...

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Identification of novel GLI1 target genes and regulatory circuits in human cancer cells

et al. 2018

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Hedgehog (HH) signaling is involved in many physiological processes, and pathway deregulation can result in a wide range of malignancies. Glioma‐associated oncogene 1 (GLI1) is a transcription factor and a terminal effector of the HH cascade. Despite its crucial role in tumorigenesis, our understanding of the GLI1 cellular targets is quite limited. In this study, we identified multiple new GLI1 target genes using a combination of different genomic surveys and then subjected them to in‐depth validation in human cancer cell lines. We were able to validate >90% of the new targets, which were enriched in functions involved in neurogenesis and regulation of transcription, in at least one type of follow‐up experiment. Strikingly, we found that RNA editing of GLI1 can modulate effects on the targets. Furthermore, one of the top targets, FOXS1, a gene encoding a transcription factor previously implicated in nervous system development, was shown to act in a negative feedback loop limiting the cellular effects of GLI1 in medulloblastoma and rhabdomyosarcoma cells. Moreover, FOXS1 is both highly expressed and positively correlated with GLI1 in medulloblastoma samples of the Sonic HH subgroup, further arguing for the existence of FOXS1/GLI1 interplay in human tumors. Consistently, high FOXS1 expression predicts longer relapse‐free survival in breast cancer. Overall, our findings open multiple new avenues in HH signaling pathway research and have potential for translational implications.

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Regulation of Gli1 Transcriptional Activity in the Nucleus by Dyrk1

Cited by 177 publications

References 51 publications

Mirk/dyrk1B Kinase Destabilizes Cyclin D1 by Phosphorylation at Threonine 288

Mirk/dyrk1B Kinase Destabilizes Cyclin D1 by Phosphorylation at Threonine 288

DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1

Identification of novel GLI1 target genes and regulatory circuits in human cancer cells

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