p38 MAP kinase negatively regulates cyclin D1 expression in airway smooth muscle cells

2001 ◽  
Vol 280 (5) ◽  
pp. L955-L964 ◽  
Author(s):  
Kristen Page ◽  
Jing Li ◽  
Marc B. Hershenson
Keyword(s):  
Growth Factor ◽  
Map Kinase ◽  
Cyclin D1 ◽  
Growth Regulation ◽  
P38 Map Kinase ◽  
Dominant Negative ◽  
Platelet Derived Growth Factor ◽  
Airway Smooth Muscle Cells ◽  
Erk Activation ◽  
Erk Phosphorylation

We have demonstrated that platelet-derived growth factor (PDGF) stimulates p38 mitogen-activated protein (MAP) kinase activation in bovine tracheal myocytes, suggesting that p38 is involved in growth regulation. We therefore examined whether p38 regulates expression of cyclin D1, a G1 cyclin required for cell cycle traversal. The chemical p38 inhibitors SB-202190 and SB-203580 each increased basal and PDGF-induced cyclin D1 promoter activity and protein abundance. Overexpression of a dominant negative allele of MAP kinase kinase-3 (MKK3), an upstream activator of p38α, had similar effects. Conversely, active MKK3 and MKK6, both of which increase p38α activity, each decreased transcription from the cyclin D1 promoter. Together, these data demonstrate that p38 negatively regulates cyclin D1 expression. We tested whether p38 regulates cyclin D1 expression via inhibition of extracellular signal-regulated kinase (ERK) activation. Chemical inhibitors of p38 induced modest ERK phosphorylation and activation. However, dominant negative MKK3 was insufficient to activate ERK, and active MKK3 and MKK6 did not attenuate platelet-derived growth factor-mediated ERK activation. These data are consistent with the notion that p38α negatively regulates cyclin D1 expression via an ERK-independent pathway.

scholarly journals Inhibitory effects of adiponectin on platelet-derived growth factor-induced mesangial cell migration

2009 ◽  
Vol 202 (2) ◽  
pp. 309-316 ◽  
Author(s):  
Keisuke Ishizawa ◽  
Narantungalag Dorjsuren ◽  
Yuki Izawa-Ishizawa ◽  
Rika Sugimoto ◽  
Yasumasa Ikeda ◽  
...  
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Map Kinase ◽  
Intracellular Signaling ◽  
Mesangial Cell ◽  
Kinase Inhibitor ◽  
P38 Map Kinase ◽  
Platelet Derived Growth Factor ◽  
Dependent Manner ◽  
Plasma Adiponectin

Adiponectin, an adipocyte-derived hormone, has been involved in metabolic syndrome, a known risk factor for the development of chronic kidney disease (CKD). Recent studies have demonstrated that plasma adiponectin levels are elevated when kidney function declines in patients with CKD. Excessive mesangial cell (MC) turnover is one of the important features of CKD. The aim of the present study is to elucidate the effects of adiponectin on platelet-derived growth factor (PDGF)-induced cell migration and intracellular signaling pathways, in cultured rat MCs (RMCs). PDGF-induced RMC migration was significantly inhibited by the pretreatment of adiponectin. Adiponectin alone had no effect on RMC migration. Big mitogen-activated protein (MAP) kinase 1 (BMK1), p38 MAP kinase, and Akt were activated by PDGF stimulation in a time- and concentration-dependent manner in RMC. Adiponectin alone did not affect BMK1, p38 MAP kinase, and Akt phosphorylations in RMC. PDGF-induced BMK1 and p38 MAP kinase phosphorylations were significantly attenuated by the pretreatment of adiponectin in RMCs. On the other hand, the phosphorylation of Akt by PDGF was not diminished by the pretreatment of adiponectin. Adiponectin had no effects on PDGF-receptor autophosphorylation by PDGF. We also confirmed that PDGF-induced RMC migration was significantly suppressed by siBMK1 transfection or SB203580, a p38 MAP kinase inhibitor. From these findings, it is implied that the elevated plasma adiponectin levels in patients with CKD might play a compensatory role aimed at counteracting renal dysfunction related to MC disorders.

scholarly journals (-)-Epigallocatechin Gallate Reduces Platelet-Derived Growth Factor-BB-Stimulated Interleukin-6 Synthesis in Osteoblasts: Suppression of SAPK/JNK

2008 ◽  
Vol 2008 ◽  
pp. 1-8 ◽  
Author(s):  
Shinji Takai ◽  
Rie Matsushima-Nishiwaki ◽  
Seiji Adachi ◽  
Hideo Natsume ◽  
Chiho Minamitani ◽  
...  
Keyword(s):  
Growth Factor ◽  
Map Kinase ◽  
Interleukin 6 ◽  
Epigallocatechin Gallate ◽  
P38 Map Kinase ◽  
Platelet Derived Growth Factor ◽  
S6 Kinase ◽  
Jnk Pathway ◽  
P70 S6 Kinase ◽  
Mitogen Activated Protein

We previously showed that the mitogen-activated protein (MAP) kinase superfamily, p44/p42 MAP kinase, p38 MAP kinase, and stress-activated protein kinase (SAPK)/c-JunN-terminal (JNK), positively plays a part in the platelet-derived growth factor-BB- (PDGF-BB-) stimulated synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, in osteoblast-like MC3T3-E1 cells while Akt and p70 S6 kinase negatively regulates the synthesis. In the present study, we investigated whether (-)-epigallocatechin gallate (EGCG), one of the major green tea flavonoids, affects the synthesis of IL-6 in these cells and the mechanism. EGCG significantly reduced the IL-6 synthesis and IL-6 mRNA expression stimulated by PDGF-BB, EGCG reduced the PDGF-BB-stimulated IL-6 synthesis also in primary-cultured osteoblasts. EGCG had no effect on the levels of osteocalcin and osteoprotegerin in MC3T3-E1 cells. The PDGF-BB-induced autophosphorylation of PDGF receptorβwas not suppressed by EGCG. The PDGF-BB-induced phosphorylation of p44/p42 MAP kinase and p38 MAP kinase was not affected by EGCG. On the other hand, EGCG markedly suppressed the PDGF-BB-induced phosphorylation of SAPK/JNK. Finally, the PDGF-BB-induced phosphorylation of Akt and p70 S6 kinase was not affected by EGCG. These results strongly suggest that EGCG inhibits the PDGF-BB-stimulated synthesis of IL-6 via suppression of SAPK/JNK pathway in osteoblasts.

p38 MAP kinase mediates platelet-derived growth factor-stimulated migration of hepatic myofibroblasts

2002 ◽  
Vol 191 (3) ◽  
pp. 351-361 ◽  
Author(s):  
Pisit Tangkijvanich ◽  
Chintda Santiskulvong ◽  
Andrew C. Melton ◽  
Enrique Rozengurt ◽  
Hal F. Yee,
Keyword(s):  
Growth Factor ◽  
Map Kinase ◽  
P38 Map Kinase ◽  
Platelet Derived Growth Factor

Platelet-derived growth factor-BB-induced hypertrophy of peritubular smooth muscle cells is mediated by activation of p38 MAP-kinase and of Rho-kinase

2006 ◽  
Vol 207 (1) ◽  
pp. 123-131 ◽  
Author(s):  
Francesca Romano ◽  
Claudia Chiarenza ◽  
Fioretta Palombi ◽  
Antonio Filippini ◽  
Fabrizio Padula ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Map Kinase ◽  
Rho Kinase ◽  
Muscle Cells ◽  
P38 Map Kinase ◽  
Platelet Derived Growth Factor

scholarly journals HSP22 (HSPB8) positively regulates PGF2α-induced synthesis of interleukin-6 and vascular endothelial growth factor in osteoblasts

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Gen Kuroyanagi ◽  
Go Sakai ◽  
Takanobu Otsuka ◽  
Naohiro Yamamoto ◽  
Kazuhiko Fujita ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Map Kinase ◽  
Interleukin 6 ◽  
Prostaglandin F2α ◽  
P38 Map Kinase ◽  
Vascular Endothelial ◽  
Mitogen Activated Protein ◽  
Endothelial Growth Factor ◽  
Vegf Release

Abstract Background Heat shock protein 22 (HSP22) belongs to class I of the small HSP family that displays ubiquitous expression in osteoblasts. We previously demonstrated that prostaglandin F2α (PGF2α), a potent bone remodeling factor, induces the synthesis of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) via p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether HSP22 is implicated in the PGF2α-induced synthesis of IL-6 and VEGF and the mechanism of MC3T3-E1 cells. Methods MC3T3-E1 cells were transfected with HSP22-siRNA. IL-6 and VEGF release was assessed by ELISA. Phosphorylation of p44/p42 MAP kinase and p38 MAP kinase was detected by Western blotting. Results The PGF2α-induced release of IL-6 in HSP22 knockdown cells was significantly suppressed compared with that in the control cells. HSP22 knockdown also reduced the VEGF release by PGF2α. Phosphorylation of p44/p42 MAP kinase and p38 MAP kinase was attenuated by HSP22 downregulation. Conclusions Our results strongly suggest that HSP22 acts as a positive regulator in the PGF2α-induced synthesis of IL-6 and VEGF in osteoblasts.

scholarly journals Loss of T-Cell Protein Tyrosine Phosphatase Induces Recycling of the Platelet-derived Growth Factor (PDGF) β-Receptor but Not the PDGF α-Receptor

2006 ◽  
Vol 17 (11) ◽  
pp. 4846-4855 ◽  
Author(s):  
Susann Karlsson ◽  
Katarzyna Kowanetz ◽  
Åsa Sandin ◽  
Camilla Persson ◽  
Arne Östman ◽  
...  
Keyword(s):  
T Cell ◽  
Growth Factor ◽  
Cell Surface ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Dominant Negative ◽  
Platelet Derived Growth Factor ◽  
Cell Protein ◽  
Protein Tyrosine ◽  
Β Receptor

We have previously shown that the T-cell protein tyrosine phosphatase (TC-PTP) dephosphorylates the platelet-derived growth factor (PDGF) β-receptor. Here, we show that the increased PDGF β-receptor phosphorylation in TC-PTP knockout (ko) mouse embryonic fibroblasts (MEFs) occurs primarily on the cell surface. The increased phosphorylation is accompanied by a TC-PTP–dependent, monensin-sensitive delay in clearance of cell surface PDGF β-receptors and delayed receptor degradation, suggesting PDGF β-receptor recycling. Recycled receptors could also be directly detected on the cell surface of TC-PTP ko MEFs. The effect of TC-PTP depletion was specific for the PDGF β-receptor, because PDGF α-receptor homodimers were cleared from the cell surface at the same rate in TC-PTP ko MEFs as in wild-type MEFs. Interestingly, PDGF αβ-receptor heterodimers were recycling. Analysis by confocal microscopy revealed that, in TC-PTP ko MEFs, activated PDGF β-receptors colocalized with Rab4a, a marker for rapid recycling. In accordance with this, transient expression of a dominant-negative Rab4a construct increased the rate of clearance of cell surface receptors on TC-PTP ko MEFs. Thus, loss of TC-PTP specifically redirects the PDGF β-receptor toward rapid recycling, which is the first evidence of differential trafficking of PDGF receptor family members.

The ERK pathway involves positive and negative regulations of HT-29 colorectal cancer cell growth by extracellular zinc

2003 ◽  
Vol 285 (6) ◽  
pp. G1181-G1188 ◽  
Author(s):  
Ki-Sook Park ◽  
Nam-Gu Lee ◽  
Ki-Hoo Lee ◽  
Jeong Taeg Seo ◽  
Kang-Yell Choi
Keyword(s):  
Colorectal Cancer ◽  
Signal Transduction ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Cyclin D1 ◽  
Growth Regulation ◽  
Erk Pathway ◽  
Differential Growth ◽  
Erk Activation ◽  
Ht 29

Dietary zinc is an important trace element in the body and is related to both cell proliferation and growth arrest. A recent study found that extracellular zinc-sensing receptors trigger intracellular signal transduction in HT-29 human colorectal cancer cells. However, the signaling mechanism causing this growth regulation by extracellular zinc is not clearly understood. At 10- and 100-μM levels of ZnCl2 treatment, HT-29 cell growth and proliferation increased and decreased, respectively, in a minimally serum-starved medium (MSSM). A lack of significant increase in intracellular zinc levels after zinc treatment suggested that this differential growth regulation of HT-29 cells by extracellular zinc is acquired by receptor-mediated signal transduction. Moreover, this zinc-induced growth regulation was differentially affected by PD-98059, suggesting the involvement of the ERK pathway. Transient ERK activation and subsequent cyclin D1 induction were observed on adding 10 μM ZnCl2 in MSSM in the presence of cell proliferation. On the other hand, prolonged ERK activity was observed with a subsequent increase of cyclin D1 and p21Cip/WAF1 on adding 100 μM ZnCl2 in MSSM, and this was associated with nonproliferation. Moreover, this ERK activation and cyclin D1 and p21Cip/WAF1 induction were abolished by PD-98059 pretreatment. The differential regulations of cell growth, ERK activities, and cyclin D1 and p21Cip/WAF1 inductions were also observed in serum-enriched medium containing higher zinc concentrations. Therefore, differential cell cycle regulator induction occurs by a common ERK pathway in the differential growth regulation of HT-29 cells by extracellular zinc.

scholarly journals Epidermal growth factor and Ras regulate gene expression in GH4 pituitary cells by separate, antagonistic signal transduction pathways.

1995 ◽  
Vol 15 (12) ◽  
pp. 6777-6784 ◽  
Author(s):  
C A Pickett ◽  
A Gutierrez-Hartmann
Keyword(s):  
Signal Transduction ◽  
Transcription Factors ◽  
Growth Factor ◽  
Map Kinase ◽  
Dominant Negative ◽  
Neuroendocrine Cells ◽  
Dependent Manner ◽  
Epidermal Growth ◽  
Dose Dependent

We have previously demonstrated that epidermal growth factor (EGF) produces activation of the rat prolactin (rPRL) promoter in GH4 neuroendocrine cells via a Ras-independent mechanism. This Ras independence of the EGF response appears to be cell rather than promoter specific. Oncogenic Ras also produces activation of the rPRL promoter when transfected into GH4 cells and requires the sequential activation of Raf kinase, mitogen-activated protein (MAP) kinase, and c-Ets-1/GHF-1 to mediate this response. In these studies, we have investigated the interaction between EGF and Ras in stimulating rPRL promoter activity and the role of Raf and MAP kinases in mediating the EGF response. We have also examined the role of several transcription factors and used various promoter mutants of the rPRL gene in order to better define the trans- and cis-acting components of the EGF response. EGF treatment of GH4 cells inhibits activation of the rPRL promoter produced by transfection of V12Ras from 24- to 4-fold in an EGF dose-dependent manner. This antagonistic effect of EGF and Ras is mutual in that transfection of V12Ras also blocks EGF-induced activation of the rPRL promoter in a Ras dose-dependent manner, from 5.5- to 1.6-fold. Transfection of a plasmid encoding the dominant-negative Raf C4 blocks Ras-induced activation by 66% but fails to inhibit EGF-mediated activation of the rPRL promoter. Similarly, transfection of a construct encoding an inhibitory form of MAP kinase decreases the Ras response by 50% but does not inhibit the EGF response. Previous studies have demonstrated that c-Ets-1 is necessary and that GHF-1 acts synergistically with c-Ets-1 in the Ras response of the rPRL promoter. In contrast, overexpression of neither c-Ets-1 nor GHF-1 enhanced EGF-mediated activation of the rPRL promoter, and dominant-negative forms of these transcription factors failed to inhibit the EGF response. Using 5' deletion and site-specific mutations, we have mapped the EGF response to two regions on the proximal rPRL promoter. One region maps between -255 and -212, near the Ras response element, and a second maps between -125 and -54. The latter region appears to involve footprint 2, a previously identified repressor site on the rPRL promoter. Neither footprint 1 nor 3, known GHF-1 binding sites, appears to be crucial to RGF-mediated rPRL promoter activation. The results of these studies indicate that in GH4 neuroendocrine cells, rPRL gene regulation by EGF is mediated by a signal transduction pathway that is separate and antagonistic to the Ras pathway. Hence, the functional role of the Ras/Raf/MAP kinase pathway in mediating transcriptional responses to EGF and other receptor tyrosine kinase may differ in highly specialized cell types.

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