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receptor up-regulation post-PDGF-BB treatment in mouse hepatic Stellate cells
1 Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, United States
2 Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, United States; Experimental Pathology Section, Department of Clinical Investigation, Walter Reed Army Medical Center, Washington, District of Columbia, United States
3 Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, District of Columbia, United States; Ciencias de la Salud, Universidad Autonoma Metropolitana, Iztapalapa, Distrito Federal, Mexico
4 Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, District of Columbia, United States
5 Biochemistry and Molecular Biology, Geroge Washington University Medical Center, Washington, District of Columbia, United States
6 Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, District of Columbia, United States; Experimental Pathology Section, Department of Clinical Investigation, Walter Reed Army Medical Center, Washington, District of Columbia, United States; Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, United States
* To whom correspondence should be addressed. E-mail: bcmmmr{at}gwumc.edu.
Increased expression of PDGF-
receptors is a landmark of hepatic stellate cell activation and trans-differentiation into myofibroblasts. However, the molecular mechanisms that regulate the fate of the receptor are lacking. Recent studies suggested that N-acetylcysteine enhances the extracellular degradation of PDGF- receptor by cathepsin B, thus suggesting that the absence of PDGF- receptors in quiescent cells is due to an active process of elimination and not to a lack of expression. In this communication we investigated further molecular mechanisms involved in PDGF- receptor elimination and reappearance after incubation with PDGF-BB. We showed that in culture activated hepatic stellate cells there is no internal protein pool of receptor, that the protein is maximally phosphorylated by 5 minutes and completely degraded after one hour by a lysosomal-dependent mechanism. Inhibition of receptor auto-phosphorylation by tyrphostin 1296 prevented its degradation, but several proteasomal and catepsin B inhibitors had no effect. We also showed that receptor reappearance is time and dose dependent, being more delayed in cells treated with 50 ng/ml (48 hours) as compared with 10 ng/ml (24 hours).
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  S. L. Friedman Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver Physiol Rev, January 1, 2008; 88(1): 125 - 172. [Abstract] [Full Text] [PDF]
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