Parathyroid Hormone–Related Protein Induces Insulin Expression Through Activation of MAP Kinase–Specific Phosphatase-1 That Dephosphorylates c-Jun NH2-Terminal Kinase in Pancreatic β-Cells

Zhang, Bin; Hosaka, Masahiro; Sawada, Yohei; Torii, Seiji; Mizutani, Shin; Ogata, Masato; Izumi, Tetsuro; Takeuchi, Toshiyuki

doi:10.2337/diabetes.52.11.2720

Cited by 35 publications

(36 citation statements)

References 58 publications

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“…To confirm the involvement of MKP-1 in the attenuating effect of PTH on MAPK phosphorylation, Ro 31-8220, an inhibitor of MKP-1 expression, was administered (14,17,18). We confirmed that Ro 31-8220 inhibited PTH-induced MKP-1 mRNA and protein expression in our model (Figure 7).…”

Section: Effect Of Actinomycin D and Ro 31-8220 On Pth-induced Attenusupporting

confidence: 57%

“…The recent characterization of dual-specific phosphatases as immediateearly gene products (14,15) with rapid transcriptional induction and short half-lives due to rapid degradation by the 26S proteasome (19) made the members of the MKP subclass of this phosphatase family interesting candidate mediators of PTHinduced MAPK dephosphorylation. Indeed, we were able to demonstrate that PTH rapidly and transiently induces gene transcription and protein synthesis of MKP-1 in UMR106-01 osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

“…The MAPK are dephosphorylated by a family of dualspecific phosphatases, which target both phosphotyrosine and phospho-serine/-threonine residues (13). PTH-related protein (PTHrP) has recently been shown to induce MAPK phosphatase (MKP)-1 in pancreatic ␤ cells (14). MKP-1 has recently been demonstrated to be upregulated by glucocorticoids in osteoblastic cells, with concurrent inactivation of p42/44 MAPK and reduction of osteoblast proliferation (15).…”

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confidence: 99%

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Mechanisms of Mitogen-Activated Protein Kinase Inhibition by Parathyroid Hormone in Osteoblast-Like Cells

Hömme

Schmitt

Mehls

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Parathyroid hormone (PTH) dose dependently inhibits growth factor-and stress-induced osteoblast proliferation via inactivating mitogen-activated protein kinase (MAPK) signaling pathways. Osteoblasts have recently been shown to express MAPK phosphatase (MKP)-1, a dual-specific phosphatase inactivator of MAPK. Investigated was the role of MKPs in the PTH-induced attenuation of MAPK and Jun N-terminal kinase (JNK) signaling in osteoblast-like UMR106-01 cells. PTH induced a persistent inhibition of p42/44 MAPK and JNK phosphorylation starting at 10 min of incubation and lasting for at least 2 h. Actinomycin D affected both p42/44 MAPK and JNK dephosphorylation by PTH, suggesting a transcription-dependent mechanism of action. PTH rapidly and transiently induced expression of MKP-1. MKP-1 mRNA was already elevated after 10 min of 10 Ϫ7 M PTH incubation, reached maximal expression after 30 to 60 min, and remained elevated after 4 h. MKP-1 protein was also upregulated within 30 to 60 min of PTH administration. The protein kinase A inhibitor H89 partly reduced PTHinduced MKP-1 expression, but the protein kinase C inhibitor bisindolylmaleimide had no effect, suggesting that PTH induces MKP-1 mainly via the protein kinase A pathway. MKP-2 mRNA was downregulated after 2 h after an early period of induction, and MKP-3 mRNA was immediately reduced. Ro 318-220 did not affect PTH-induced MAPK inactivation but effectively blocked JNK dephosphorylation. The time course of PTH-induced MKP-1 protein expression closely correlated with JNK dephosphorylation. PTH attenuates the stress-induced JNK signaling pathway in osteoblasts via induction of MKP-1 synthesis but inhibits the p42/44 MAPK pathway mainly via transcription-independent mechanisms.

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Section: Effect Of Actinomycin D and Ro 31-8220 On Pth-induced Attenusupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Mechanisms of Mitogen-Activated Protein Kinase Inhibition by Parathyroid Hormone in Osteoblast-Like Cells

Hömme

Schmitt

Mehls

et al. 2004

Journal of the American Society of Nephrology

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“…HIT-T15, 10 mmol/l (Santerre et al 1981); INS-1, 11 . 1 mmol/l (Asfari et al 1992); MIN-6, 25 mmol/l (Miyazaki et al 1990, Lilla et al 2003, O'Driscoll et al 2004; and isolated murine islets, 25 mmol/l (Zhang et al 2003), although it should be noted that many researchers culture murine islets in medium containing 5 . 6 or 11 mM glucose.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic and global gene expression profile changes between low passage and high passage MIN-6 cells

O’Driscoll¹,

Gammell²,

McKiernan³

et al. 2006

Journal of Endocrinology

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The long-term potential to routinely use replacement b cells/islets as cell therapy for type 1 diabetes relies on our ability to culture such cells/islets, in vitro, while maintaining their functional status. Previous b cell studies, by ourselves and other researchers, have indicated that the glucosestimulated insulin secretion (GSIS) phenotype is relatively unstable, in long-term culture. This study aimed to investigate phenotypic and gene expression changes associated with this loss of GSIS, using the MIN-6 cell line as model. Phenotypic differences between MIN-6(L, low passage) and MIN-6(H, high passage) were determined by ELISA (assessing GSIS and cellular (pro)insulin content), proliferation assays, phase contrast light microscopy and analysis of alkaline phosphatase expression. Differential mRNA expression was investigated using microarray, bioinformatics and real-time PCR technologies. Long-term culture was found to be associated with many phenotypic changes, including changes in growth rate and cellular morphology, as well as loss of GSIS. Microarray analyses indicate expression of many mRNAs, including many involved in regulated secretion, adhesion and proliferation, to be significantly affected by passaging/ long-term culture. Loss/reduced levels, in high passage cells, of certain transcripts associated with the mature b cell, together with increased levels of neuron/glia-associated mRNAs, suggest that, with time in culture, MIN-6 cells may revert to an early (possibly multi-potential), poorly differentiated, 'precursorlike' cell type. This observation is supported by increased expression of the stem cell marker, alkaline phosphatase.

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“…The aim of this study was to examine differential regulation of the proteome associated with continuous culture of MIN-6 cells and corresponding loss of GSIS phenotype to enable future development of potential methods whereby relevant beta cell functions could be preserved in long-term culture [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Proteomic screening of glucose-responsive and glucose non-responsive MIN-6 beta cells reveals differential expression of proteins involved in protein folding, secretion and oxidative stress

et al. 2006

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The glucose-sensitive insulin-secretion (GSIS) phenotype is relatively unstable in long-term culture of beta cells. The purpose of this study was to investigate relative changes in the proteome between glucose-responsive (low passage) and glucose non-responsive (high passage) murine MIN-6 pancreatic beta cells. The 2D-DIGE and subsequent DeCyder analysis detected 3351 protein spots in the pH range of 4-7. Comparing MIN-6(H) to MIN-6(L) and using a threshold of 1.2-fold, the number of proteins with a decrease in expression level was 152 (4.5%), similar was 3140 (93.7%) and increased 59 (1.8%). From the differentially expressed proteins identified in this study, groups of proteins associated with the endoplasmic reticulum (ER) and proteins involved in oxidative stress were found to be significantly decreased in the high-passage (H passage) cells. These proteins included endoplasmic reticulum protein 29 (ERp29); 78-kDa glucoserelated protein, (GRP78); 94-kDa glucose-related protein (GRP94); protein disulphide isomerase; carbonyl reductase 3; peroxidoxin 4 and superoxide dismutase 1. These results suggest that non-GSIS MIN-6 cells do not have the same ability/capacity of glucose-responsive MIN-6 cells to successfully fold, modify or secrete proteins and counteract the problems associated with oxidative stress.

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Parathyroid Hormone–Related Protein Induces Insulin Expression Through Activation of MAP Kinase–Specific Phosphatase-1 That Dephosphorylates c-Jun NH2-Terminal Kinase in Pancreatic β-Cells

Cited by 35 publications

References 58 publications

Mechanisms of Mitogen-Activated Protein Kinase Inhibition by Parathyroid Hormone in Osteoblast-Like Cells

Mechanisms of Mitogen-Activated Protein Kinase Inhibition by Parathyroid Hormone in Osteoblast-Like Cells

Phenotypic and global gene expression profile changes between low passage and high passage MIN-6 cells

Proteomic screening of glucose-responsive and glucose non-responsive MIN-6 beta cells reveals differential expression of proteins involved in protein folding, secretion and oxidative stress

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