The Stress-activated Protein Kinases p38α and JNK1 Stabilize p21Cip1 by Phosphorylation

Kim, Geum Yi; Mercer, Stephen E.; Ewton, Daina Z.; Yan, Zhong; Jin, Kideok; Friedman, Eileen

doi:10.1074/jbc.m201299200

Cited by 213 publications

(213 citation statements)

References 41 publications

(46 reference statements)

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“…Initial in vitro experiments suggested that Mirk phosphorylated cyclin D1 at Thr 184 , Thr 288 , or both residues (data not shown). However, the activity of kinases can be very different in vitro and in vivo (21), so these experiments were taken only as guides for subsequent studies.…”

Section: Resultsmentioning

confidence: 99%

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

Zou

Ewton

Deng

et al. 2004

Journal of Biological Chemistry

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110

128

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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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Section: Resultsmentioning

confidence: 99%

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

Zou

Ewton

Deng

et al. 2004

Journal of Biological Chemistry

Self Cite

110

128

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“…Actually, Raf/MEK/ ERK and MKK3/6-p38 represent two independent mitogen-activated protein kinase (MAPK) pathways. Whereas the Raf/MEK/ERK cascade transduces proliferative signals, the MKK3/6-p38 cascade is a major mediator of stress responses that usually leads to growth arrest or apoptosis (Kim et al, 2002;Xiu et al, 2003;Bulavin and Fornace, 2004;Yee et al, 2004). It was reported that the MKK3/6-p38 cascade functions as downstream of the Raf/MEK/ERK cascade to mediate senescence.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

Wang

Liu

et al. 2010

Oncogene

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Oncogene-mediated premature senescence has emerged as a potential tumor-suppressive mechanism in early cancer transitions. Many studies showed that Ras and p38 mitogen-activated protein kinase (MAPK) participate in premature senescence. Our previous work indicated that the HMG box-containing protein 1 (HBP1) transcription factor is involved in Ras-and p38 MAPK-induced premature senescence, but the mechanism of which has not yet been identified. Here, we showed that the p16 INK4A cyclin-dependent kinase inhibitor is a novel target of HBP1 participating in Ras-induced premature senescence. The promoter of the p16 INK4A gene contains an HBP1-binding site at position À426 to À433 bp from the transcriptional start site. HBP1 regulates the expression of the endogenous p16 INK4A gene through direct sequence-specific binding. With HBP1 expression and the subsequent increase of p16 INK4A gene expression, Ras induces premature senescence in primary cells. The data suggest a model in which Ras and p38 MAPK signaling engage HBP1 and p16 INK4A to trigger premature senescence. In addition, we report that HBP1 knockdown is also required for Ras-induced transformation. All the data indicate that the mechanism of HBP1-mediated transcriptional regulation is important for not only premature senescence but also tumorigenesis.

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“…These features of SIPS can result from activation of the stress-associated p38a MAP kinase as the use of the p38 selective inhibitor SB203580 prevents ras-induced senescence in human BJ fibroblasts (Deng et al 2004;Wang et al 2002). Activation of p38 leads to the stabilisation of the cyclin-dependent kinase inhibitor p21 WAF1 and subsequent cell cycle arrest, and also leads to the phosphorylation of the small heat shock protein HSP27 resulting in stress fibre formation (Deng et al 2004;Haq et al 2002;Kim et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Assessing the role of stress signalling via p38 MAP kinase in the premature senescence of Ataxia Telangiectasia and Werner syndrome fibroblasts

Davis

Kipling

2008

Biogerontology

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The premature ageing Ataxia Telangiectasia (AT) and Werner syndromes (WS) are associated with accelerated cellular ageing. Young WS fibroblasts have an aged appearance and activated p38 MAP kinase, and treatment with the p38 inhibitor SB230580 extends their lifespan to within the normal range. SB203580 also extends the replicative lifespan of normal adult dermal fibroblasts, however, the effect is much reduced when compared to WS cells, suggesting that WS fibroblasts undergo a form of stress-induced premature senescence (SIPS). A small lifespan extension is seen in AT cells, which is not significant compared to normal fibroblasts, and the majority of young AT cells do not have an aged appearance and lack p38 activation, suggesting that the premature ageing does not result from SIPS. The lack of p38 activation is supported by the clinical manifestation, since AT is not associated with inflammatory disease, whereas WS individuals are predisposed to atherosclerosis, type II diabetes and osteoporosis, conditions known to be associated with p38 activation.

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The Stress-activated Protein Kinases p38α and JNK1 Stabilize p21Cip1 by Phosphorylation

Cited by 213 publications

References 41 publications

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

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

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

Assessing the role of stress signalling via p38 MAP kinase in the premature senescence of Ataxia Telangiectasia and Werner syndrome fibroblasts

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