Vascular smooth muscle cell proliferation requires both p38 and BMK1 MAP kinases

Zhao, Ming; Liu, Yawei; Bao, Mingmin; Kato, Yasuhiro; Han, Jiahuai; Eaton, John W.

doi:10.1016/s0003-9861(02)00028-0

Cited by 46 publications

(42 citation statements)

References 43 publications

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“…The role of p38 MAPK in the regulation of proliferation has been extensively studied [32], however the relationship varies with cell type. For example, p38 MAPK activation is linked with increased proliferation in vascular smooth muscle cells [33], is necessary for the fibroblast growth factor-2 stimulation of fibroblasts [21], but arrests proliferation of thymocytes [9]. The current studies show that in human chondrocytes, inhibition of p38 MAPK enhances growth factor stimulated proliferation, and can increase, but not restore, proliferation in IL-1 activated cells.…”

Section: Discussionmentioning

confidence: 60%

p38 MAPK and COX2 inhibition modulate human chondrocyte response to TGF‐β

Studer

Chu

2005

Journal Orthopaedic Research

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These studies compare actions of p38 MAPK inhibition and COX2 inhibition to modulate human arthritic chondrocyte responses to TGF-P and FCS under basal and IL-1 activated conditions.Chondrocytes isolated from arthritic human femoral condyle cartilage obtained at total knee ,replacement were grown to 80% confluence. Proteoglycan synthesis and proliferation were measured with and without IL-1 activation in the presence and absence of growth factors and with and without inhibition of p38 MAPK or COX2 activity. Experiments to evaluate TIMP-1 production under these conditions were done using cartilage organ cultures.Neither p38 MAPK inhibitors nor COX2 inhibition affected basal proliferation. However both inhibitors enhanced the proliferative response to TGF-P and FCS in IL-I activated chondrocytes. TGF-P stimulated proteoglycan synthesis was decreased by p38 MAPK inhibition, however COX2 inhibition restored the response to TGF-P in IL-1 activated cells. In contrast, COX2 inhibition did not modulate TIMP-I production while p38 MAPK inhibitors potentiated TGF-f3 stimulated production of TIMP-1 in IL-1 activated cartilage.p38 MAPK inhibition and COX2 inhibition have unique and similar abilities to counteract some of the effects of IL-1 on human chondrocyte/cartilage metabolism. Both will partially restore the proliferative response to growth factors. p38 MAPK inhibition blunts TGF-P stimulation of proteoglycan synthesis, but increases TIMP-1 synthesis. COX2 inhibition can restore the proteoglycan synthetic response to TGF-P, but has no effect on cartilage TIMP-1 production. Use of these inhibitors to minimize cartilage damage in arthritic and mechanically stressed joints should reflect these characteristics.

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Section: Discussionmentioning

confidence: 60%

p38 MAPK and COX2 inhibition modulate human chondrocyte response to TGF‐β

Studer

Chu

2005

Journal Orthopaedic Research

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“…10D). This pathway may also be relevant to macrophage activation (75), vascular smooth muscle proliferation (12), and excitation-dependent neuron survival (76), as each also involves gene regulation by p38 signaling through MEF2 factors. MEF2A is also a substrate for Erk5, and the resulting Ser/Thr phosphorylations stimulate factor trans-activity by SUMOylation-dependent and independent means.…”

Section: Discussionmentioning

confidence: 99%

“…MEF2A is also a substrate for Erk5, and the resulting Ser/Thr phosphorylations stimulate factor trans-activity by SUMOylation-dependent and independent means. 7 The Erk5 3 MEF2 pathway is necessary for muscle differentiation (77), neuron survival (78), and smooth muscle proliferation (12). We propose that these processes also involve positive transcriptional autoregulation of MEF2A.…”

Section: Discussionmentioning

confidence: 99%

“…It is now apparent that these factors play many roles in various tissues and cell types, both during development and after terminal differentiation. MEF2 proteins contribute to the orchestration of skeletal muscle differentiation (6,7) and fiber type programming (8,9), cardiac development and hypertrophy (10,11), and vascular development and smooth muscle proliferation (12)(13)(14). These factors are also involved in excitation-dependent neuron survival (15,16) and synapse formation (17,18).…”

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Myocyte Enhancer Factor 2A Is Transcriptionally Autoregulated

Ramachandran

et al. 2008

Journal of Biological Chemistry

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MEF2 (myocyte enhancer factor 2) proteins are a small family of transcription factors that play pivotal roles in striated muscle differentiation, development, and metabolism, in neuron survival and synaptic formation, and in lymphocyte selection and activation. Products of the four mammalian MEF2 genes, MEF2A, MEF2B, MEF2C, and MEF2D, are expressed with overlapping but distinct temporospatial patterns. Toward analysis of MEF2A functions and the determinants of its regulated expression, we have mapped and begun studies of the transcriptional control regions of this gene. Heterogeneous 5 -untranslated regions of MEF2A mRNAs result from use of alternative promoters and splicing patterns. The two closely approximated TATA-less promoters are ϳ65 kb upstream of the exon containing the sole initiation codon. Ribonuclease protection and primer extension assays show that each promoter is active in various adult tissues. A canonical MEF2 site overlies the major promoter 1 transcription start site. This element specifically binds MEF2 factors, including endogenous nuclear MEF2A according to chromatin immunoprecipitation studies, and is critical to MEF2A transcription in myocytes. The site exerts reciprocal control of the alternative promoters, silencing promoter 1 and activating promoter 2 under some conditions. Erk5 and p38 MAPK signaling stimulate MEF2A expression by activating both promoters from the MEF2 element. MEF2A transcription is therefore subject to positive or negative regulation by its protein products, depending on signaling activities that influence MEF2 factor trans-activity. The sole MEF2 gene of the cephalochordate amphioxus has a similar regulatory region structure, suggesting that this mode of autoregulatory control is conserved among higher metazoan MEF2 genes.

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“…For example, there is evidence for a role of p38 in the regulation of cyclin D1 protein ubiquitination and subsequent degradation through direct phosphorylation of a threonine residue (Casanovas et al, 2000). Furthermore, both positive (Crawley et al, 1997;Maher, 1999;Juretic et al, 2001;Recio and Merlino, 2002;Zhao et al, 2002) and negative (Diehl et al, 2000;Puri et al, 2000;Alderton et al, 2001;Smalley and Eisen, 2002) roles of p38 in cell proliferation have been described, suggesting that the mitogenic and antimitogenic functions of p38 are dependent on the cell type and possibly other factors.…”

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confidence: 99%

p38 MAP kinase signaling is necessary for rat chondrosarcoma cell proliferation

et al. 2004

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Chondrosarcomas represent the second most frequent class of primary skeletal malignancies. This tumor type is highly resistant to radiation therapy and currently available chemotherapies, thereby limiting treatment choice to surgical resection. Identifying the mechanisms responsible for chondrosarcoma cell proliferation is therefore crucial for the development of new treatment strategies. Here, we demonstrate a significant reduction in rat chondrosarcoma cell proliferation following treatment with pharmacological inhibitors (SB202190 and PD169316) of p38 mitogen-activated protein (MAP) kinases. In an attempt to dissect possible mechanisms, we investigated the effect of p38 inhibition on promoter activity of cell-cycle genes. Surprisingly, p38 inhibition resulted in upregulation of the activities of all three D-type cyclin promoters. In addition, p38 inhibitors induced increased transcription of the cell-cycle inhibitor p21 waf1/cip1 . As expected, promoter activity of the cyclin A gene, which lies downstream of D-type cyclins and p21 in cell-cycle progression, was strongly reduced by p38 inhibitors. These effects were independent of a cyclic AMP response element and conferred by the proximal 150 nucleotides of the cyclin A promoter. Decreased transcription was accompanied by greatly reduced cyclin A protein levels upon p38 inhibition. These observations indicate complex regulation of chondrosarcoma cell-cycle progression by p38 signaling, and suggest that components of p38 MAP kinase pathways may be effective targets in the treatment of these tumors.

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Vascular smooth muscle cell proliferation requires both p38 and BMK1 MAP kinases

Cited by 46 publications

References 43 publications

p38 MAPK and COX2 inhibition modulate human chondrocyte response to TGF‐β

p38 MAPK and COX2 inhibition modulate human chondrocyte response to TGF‐β

Myocyte Enhancer Factor 2A Is Transcriptionally Autoregulated

p38 MAP kinase signaling is necessary for rat chondrosarcoma cell proliferation

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