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Cellular activity of the myosin light chain phosphatase (MLCP) determines agonist-induced force development of smooth muscle (SM). CPI-17 is an endogenous inhibitor protein for MLCP, responsible for mediating G-protein signaling into SM contraction. Fluctuations in CPI-17 expression occur in response to pathological stresses, altering excitation-contraction coupling in SM. Here, we determined the signaling pathways regulating CPI-17 expression in rat aorta tissues and the cell culture using a pharmacological approach. CPI-17 transcription was suppressed in response to the proliferative stimulus with platelet-derived growth factor (PDGF) through the ERK1/2 pathway, whereas it was elevated in response to inflammatory, stress-induced and excitatory stimuli with transforming growth factor-β, IL-1β, TNFα, sorbitol, and serotonin. CPI-17 transcription was repressed by inhibition of JNK, p38, PKC, and Rho-kinase (ROCK). The mouse and human CPI-17 gene promoters were governed by the proximal GC-boxes at the 5'-flanking region, where Sp1/Sp3 transcription factors bound. Sp1 binding to the region was more prominent in intact aorta tissues, compared with the SM cell culture, where the CPI-17 gene is repressed. The 173-bp proximal promoter activity was negatively and positively regulated through PDGF-induced ERK1/2 and sorbitol-induced p38/JNK pathways, respectively. By contrast, PKC and ROCK inhibitors failed to repress the 173-bp promoter activity, suggesting distal enhancer elements. CPI-17 transcription was insensitive to knockdown of myocardin/Kruppel-like factor 4 small interfering RNA or histone deacetylase inhibition. The reciprocal regulation of Sp1/Sp3-driven CPI-17 expression through multiple kinases may be responsible for the adaptation of MLCP signal and SM tone to environmental changes.

american journal of physiology. cell physiology

Reciprocal regulation controlling the expression of CPI-17, a specific inhibitor protein for the myosin light chain phosphatase in vascular smooth muscle cells