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inhibition of proteasomal activity. A potential mechanism of growth arrest
1 Department of Internal Medicine, Scott and White Clinic, Texas A&M University HSC College of Medicine, Temple, TX, USA
2 Department of Medical Physiology, Texas A&M University System HSC College of Medicine, Temple, TX, USA
* To whom correspondence should be addressed. E-mail: tpatel{at}medicine.tamu.edu.
Although the proteasome plays a critical role in the controlled degradation of proteins involved in cell cycle control, the direct modulation of proteasomal function by growth regulatory signaling has not yet been demonstrated. We assessed the effect of Transforming Growth Factor-
(TGF), a potent inhibitor of cell growth, on proteasomal function. TGF selectively decreased hydrolysis of the proteasomal substrate z-Leu-Leu-Leu-AMC (z-LLL-AMC) in a concentration dependent manner but did not inhibit hydrolysis of other substrates Suc-Leu-Leu-Val-Tyr (suc-LLVY-AMC) or z-Leu-Leu-Gln-AMC (z-LLE-AMC). An increase in intracellular oxidative injury occurred during incubation with TGF. Furthermore in vitro hydrolysis of z-LLL-AMC, but not suc-LLVY-AMC, was decreased by hydrogen peroxide. TGF did not increase cellular expression of hsp90, a potent inhibitor of z-LLL-AMC hydrolysis in vitro. The physiological relevance of TGF inhibition of proteasomal activity was studied by assessing the role of z-LLL-AMC hydrolysis on cyclin dependent kinase inhibitor expression and cell growth. TGF increased expression of p27KIP1 but did not alter expression of p21WAF1 or p16INK4A. The peptide aldehyde Cbz-Leu-Leu-Leucinal (LLL-CHO or MG132) potently inhibited z-LLL-AMC hydrolysis in cell extracts as well as increased p27KIP1 and decreased cell proliferation. Thus growth inhibition by TGF decreases a specific proteosomal activity via an hsp90 independent mechanism that may involve oxidative inactivation or modulation of proteasomal subunit composition, and results in altered cellular expression of key cell cycle regulatory proteins such as p27KIP1.
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