High-Level Expression of the Mnb/Dyrk1A Gene in Brain and Heart during Rat Early Development

Okui, Masayuki; Ide, Toshinori; Morita, Keiichi; Funakoshi, Eishi; Ito, F.; Ogita, Kiyokazu; Yoneda, Yukio; Kudoh, Jun; Shimizu, Nobuyoshi

doi:10.1006/geno.1999.5998

Cited by 85 publications

(67 citation statements)

References 16 publications

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“…37 DYRK1A is expressed in several brain regions and also in several adult tissues such as heart, liver, lung, spleen and kidney, etc. 38 de Wit et al (2002) reported that Dyrk1a is highly expressed in melanoma cell and lesion but at low levels in normal samples as detected by high-density oligonucleotide arrays and Northern blotting. 39 This widespread but not ubiquitous expression pattern suggests diverse functions of DYRK1A throughout life and during tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of Dyrk1a in HPV16 immortalized Keratinocytes enable evasion of apoptosis

Chang

Lin

Yang

et al. 2007

Intl Journal of Cancer

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Immortalization is a critical event in virus-related oncogenesis. No enough information, however, is currently available to elucidate the changes that occur in cellular molecules during immortalization. To identify potential cellular markers or regulators involving in immortalization, a paired-cell model of primary foreskin keratinocytes (FK) and HPV16 immortalized foreskin keratinocytes were established. Using mRNA differential display, RT-PCR and Northern blot methods, we have identified and confirmed that Dyrk1a (dual-specificity tyrosine-phosphorylated and regulated kinase 1A) is present and increased in HPV16 immortalized cells, but is absent in primary keratinocytes. Moreover, transfection of E7 siRNA oligo into immortalized cells leads to a diminishing E7 expression and the eventual disappearance of Dyrk1a. Similar results of Dyrk1a expressional differences could also be seen when tissue specimens were compared using LCM/real-time PCR and immunohistochemistry analysis; malignant cervical lesions contain significantly more DYRK1A than normal tissue. It was also demonstrated that raised DYRK1A could rearrange the cellular localization of FKHR (forkhead in rhabdomyosarcoma), an apoptosis activator, and suppress BAD. Importantly, this phenomenon can be reversed when endogenous Dyrk1a was knocked down in immortalized cells by RNA interference. These results suggest that the raised Dyrk1a in HPV16 immortalized keratinocytes and cervical lesions may serve as a candidate antiapoptotic factor in the FKHR regulated pathway and initiate immortalization and tumorigenesis gradually. ' 2007 Wiley-Liss, Inc.Key words: HPV16; keratinocytes; Dyrk1a; immortalization; apoptosis Mammalian cells have a limited life span and proliferating capacity when cultivated in vitro. Replicate senescence or the terminal arrest state, has been found to be accompanied by several molecular changes that lead to an activated suppression of the cell cycle and the shortening of the telomeres. 1 Similar to apoptosis, cellular senescence is thought to be a mechanism of tumor suppression because it prevents the outgrowth of cells that have acquired mutations in genes rendering them cancerous. Consistent with this model, several tumor suppressor genes (such as, overexpressed p16 or ZNF217, activated p53 and deregulated Rassf1a or c-myc, etc) or their products have been reported and shown to be associated in parallel with telomere irregularities at the onset of cellular senescence. 2 Telomere shortening has been shown to generate unstable DNA leading to p53 activation and the subsequent transcriptional induction of the cdk inhibitor p21 CIP13 that moves cells into senescence state. Therefore, preventing telomere erosion by ectopic expression of telomerase is sufficient to immortalized primary cells in vitro and thus extend life span. [4][5][6] Although it works in human fibroblast, telemorase alone, however, is not sufficient to induce immortalization in human keratinocytes and mammary epithelial cells. 7 To identify other factors that are involved ...

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Section: Discussionmentioning

confidence: 99%

Increased expression of Dyrk1a in HPV16 immortalized Keratinocytes enable evasion of apoptosis

Chang

Lin

Yang

et al. 2007

Intl Journal of Cancer

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“…DYRK1A is ubiquitously expressed, with higher levels in brain, heart, placenta, and skeletal muscle (24,39,40). The closely related family member, DYRK1B, is expressed in skeletal muscle, testes (21,41), and several types of cancer cells (41).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Ser640 in Muscle Glycogen Synthase by DYRK Family Protein Kinases

Skurat

Dietrich

2004

Journal of Biological Chemistry

104

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Glycogen synthase, a key enzyme in the regulation of glycogen synthesis by insulin, is controlled by multisite phosphorylation. Glycogen synthase kinase-3 (GSK-3) phosphorylates four serine residues in the COOH terminus of glycogen synthase. Phosphorylation of one of these residues, Ser 640 (site 3a), causes strong inactivation of glycogen synthase. In previous work, we demonstrated in cell models that site 3a can be phosphorylated by an as yet unidentified protein kinase (3a-kinase) distinct from GSK-3. In the present study, we purified the 3a-kinase from rabbit skeletal muscle and identified one constituent polypeptide as HAN11, a WD40 domain protein with unknown function. Another polypeptide was identified as DYRK1A, a member of the dual-specificity tyrosine phosphorylated and regulated protein kinase (DYRK) family. Two isoforms of DYRK, DYRK1A and DYRK1B, co-immunoprecipitate with HAN11 when coexpressed in COS cells indicating that the proteins interact in mammalian cells. Co-expression of DYRK1A, DYRK1B, or DYRK2 with a series of glycogen synthase mutants with Ser/Ala substitutions at the phosphorylation sites in COS cells revealed that protein kinases cause phosphorylation of site 3a in glycogen synthase. To confirm that DYRKs directly phosphorylate glycogen synthase, recombinant DYRK1A, DYRK2, and glycogen synthase were produced in bacterial cells. In the presence of Mg-ATP, both DYRKs inactivated glycogen synthase by more than 10-fold. The inactivation correlated with phosphorylation of site 3a in glycogen synthase. These results indicate that protein kinase(s) from the DYRK family may be involved in a new mechanism for the regulation of glycogen synthesis.

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“…Dual-specificity tyrosine-regulated kinase 1A (Dyrk1A) belongs to the DYRK subfamily of protein kinases, and maps to chromosome 21 (21q22.2), within the Down's syndrome critical region (DSC) (Cheon et al, 2003;Shindoh et al, 1996;Song et al, 1996). Dyrk1A is highly conserved at the protein level across vertebrates and invertebrates, being most prominently expressed in developing brain and heart (Okui et al, 1999). Evidence is accumulating that DYRK1A, one of approximately 20 genes located in this region, is important in the neurobiological alterations of Down's syndrome (Altafaj et al, 2001;Fotaki et al, 2002;Park et al, 2009;Smith et al, 1997;Tejedor and Hammerle, 2010;Wegiel et al, 2010).…”

Section: Short Report 561mentioning

confidence: 99%

Down's-syndrome-related kinase Dyrk1A modulates the p120-catenin–Kaiso trajectory of the Wnt signaling pathway

Hong

Park

Lee

et al. 2012

Journal of Cell Science

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The Wnt pathways contribute to many processes in cancer and development, with β-catenin being a key canonical component. p120-catenin, which is structurally similar to β-catenin, regulates the expression of certain Wnt target genes, relieving repression conferred by the POZ- and zinc-finger-domain-containing transcription factor Kaiso. We have identified the kinase Dyrk1A as a component of the p120-catenin–Kaiso trajectory of the Wnt pathway. Using rescue and other approaches in Xenopus laevis embryos and mammalian cells, we found that Dyrk1A positively and selectively modulates p120-catenin protein levels, thus having an impact on p120-catenin and Kaiso (and canonical Wnt) gene targets such as siamois and wnt11. The Dyrk1A gene resides within the Down's syndrome critical region, which is amplified in Down's syndrome. A consensus Dyrk phosphorylation site in p120-catenin was identified, with a mutant mimicking phosphorylation exhibiting the predicted enhanced capacity to promote endogenous Wnt-11 and Siamois expression, and gastrulation defects. In summary, we report the biochemical and functional relationship of Dyrk1A with the p120-catenin–Kaiso signaling trajectory, with a linkage to canonical Wnt target genes. Conceivably, this work might also prove relevant to understanding the contribution of Dyrk1A dosage imbalance in Down's syndrome.

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High-Level Expression of the Mnb/Dyrk1A Gene in Brain and Heart during Rat Early Development

Cited by 85 publications

References 16 publications

Increased expression of Dyrk1a in HPV16 immortalized Keratinocytes enable evasion of apoptosis

Increased expression of Dyrk1a in HPV16 immortalized Keratinocytes enable evasion of apoptosis

Phosphorylation of Ser640 in Muscle Glycogen Synthase by DYRK Family Protein Kinases

Down's-syndrome-related kinase Dyrk1A modulates the p120-catenin–Kaiso trajectory of the Wnt signaling pathway

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