Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 24, Issue 1, Pages 85-90Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.ATV.0000104012.40720.c4
Keywords
nuclear factor-kappa B; beta-TrCP1; muscle, vascular, smooth; Wnt; beta-catenin
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Objective-Degradation of IkappaB is an essential step in nuclear factor (NF)-kappaB activation. However, the determinants regulating this process have not been defined in vascular smooth muscle cells (VSMCs). We hypothesized that the E3-ligase, beta-transducin repeat-containing protein 1 (beta-TrCP1), was a rate-determining mediator that regulates the ubiquitin-mediated degradation of IomicronBalpha (in VSMC). Methods and Results-Upregulation of beta-TrCP1 accelerated the rate of IkappaBalpha degradation, leading to increased NF-kappaB activity. In contrast, VSMCs harboring a dominant-negative beta-TrCP1 transgene lacking the F-box domain exhibited a reduction in serum-stimulated NF-kB activity but no alteration in response to tumor necrosis factor (TNF). These findings suggest that beta-TrCP1 increases the rate of NF-kappaB activation but is not rate-limiting in response to TNF in VSMCs. Endogenous alpha-TrCP1 expression was regulated through the conserved Wnt cascade. Upregulation of Wnt1 resulted in beta-catenin-mediated activation of Tcf-4, leading to increased beta-TrCP1 expression and NF-kappaB activity. Furthermore, VSMCs harboring a Tcf-4 mutant lacking a beta-catenin binding domain exhibited a significant reduction in beta-TrCP1 expression along with abolishment of NF-kappaB activity. Conclusions-We provide the first evidence of crosstalk between the Wnt cascade and NF-kappaB signaling in VSMCs. This crosstalk is mediated through the E3-ligase, beta-TrCP1.
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