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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:85.)
© 2004 American Heart Association, Inc.

Vascular Biology

The Role of ß-Transducin Repeat-Containing Protein (ß-TrCP) in the Regulation of NF-B in Vascular Smooth Muscle Cells

Xiaohong Wang; Neeta Adhikari; Qinglu Li; Zhanjun Guan; Jennifer L. Hall

From the Lillehei Heart Institute, Division of Cardiology, Department of Medicine, University of Minnesota, Minneapolis.

Correspondence to Jennifer L. Hall, PhD, Assistant Professor of Medicine Director, Cardiovascular Genomics Cardiovascular Division Lillehei Heart Institute, University of Minnesota, 420 Delaware St, Minneapolis, MN 55455. E-mail Hallx068{at}umn.edu

Objective— Degradation of IB is an essential step in nuclear factor (NF)-B activation. However, the determinants regulating this process have not been defined in vascular smooth muscle cells (VSMCs). We hypothesized that the E3-ligase, ß-transducin repeat-containing protein 1 (ß-TrCP1), was a rate-determining mediator that regulates the ubiquitin-mediated degradation of IB (in VSMC).

Methods and Results— Upregulation of ß-TrCP1 accelerated the rate of IB degradation, leading to increased NF-B activity. In contrast, VSMCs harboring a dominant-negative ß-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 ß-TrCP1 increases the rate of NF-B activation but is not rate-limiting in response to TNF in VSMCs. Endogenous ß-TrCP1 expression was regulated through the conserved Wnt cascade. Upregulation of Wnt1 resulted in ß-catenin–mediated activation of Tcf-4, leading to increased ß-TrCP1 expression and NF-B activity. Furthermore, VSMCs harboring a Tcf-4 mutant lacking a ß-catenin binding domain exhibited a significant reduction in ß-TrCP1 expression along with abolishment of NF-B activity.

Conclusions— We provide the first evidence of crosstalk between the Wnt cascade and NF-B signaling in VSMCs. This crosstalk is mediated through the E3-ligase, ß-TrCP1.

Key Words: nuclear factor-B • ß-TrCP1 • muscle, vascular, smooth • Wnt • ß-catenin

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