Murine colonic mucosa hyperproliferation.: II.: PKC-β activation and cPKC-mediated cellular CFTR overexpression

被引:19
作者
Umar, S
Sellin, JH
Morris, AP [1 ]
机构
[1] Univ Texas, Hlth Sci Ctr, Sch Med, Dept Internal Med,Div Gastroenterol Hepatol & Nut, Houston, TX 77030 USA
[2] Univ Texas, Hlth Sci Ctr, Sch Med, Dept Integrat Biol Pharmacol & Physiol, Houston, TX 77030 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY | 2000年 / 278卷 / 05期
关键词
protein kinase C; cystic fibrosis transmembrane conductance; regulator; anion transport; regulation; mouse;
D O I
10.1152/ajpgi.2000.278.5.G765
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
In the companion article (Umar S, Scott J, Sellin JH, Dubinsky WP, and Morris AP, Am J Physiol Gastrointest Liver Physiol 278: 753-764, 2000), we have shown that transmissible murine colonic hyperplasia (TMCH) increased cellular cystic fibrosis transmembrane conductance regulator (CFTR) mRNA and protein expression, relocalized CFTR within colonocytes, and enhanced mucosal cAMP-dependent Cl- secretion. We show here that these changes were dependent on elevated cellular levels of membrane-bound Ca2+- and diacylglycerol-sensitive protein kinase C (PKC) activity (12-fold), induced by selective (3- to 4-fold) rises in conventional PKC (cPKC) isoform expression and membrane translocation. Three cPKC isoforms were detected in isolated crypts: alpha, beta 1, and beta 2. cPKC-beta 1 rises preceded and those of cPKC-alpha and cPKC-beta 2 paralleled cellular hyperproliferation and its effects on CFTR expression and cAMP-dependent Cl- current secretion. Only cPKC-beta 1 and cPKC-beta 2 were membrane translocated during TMCH. Furthermore, only cPKC-beta 1 trafficked to the nucleus, whereas cPKC-beta 2 remained partitioned among cytosolic, membrane, and cytoskeletal subcellular fractions. Modest increases in novel PKC-epsilon (nPKC-epsilon) expression and subcellular membrane partitioning were recorded during TMCH, but no changes were seen for PKC-delta or -eta. No nPKC isoform nuclear partitioning was detected. The orally bioactive cPKC inhibitor Re-32-0432 reversed both TMCH and elevated cellular CFTR mRNA levels, whereas a pharmacologically inert analog (Ro-31-6045) failed to inhibit either response. On the basis of these facts, we present a new hypothesis whereby PKC-dependent cellular proliferation promotes endogenous cellular CFTR levels. PKC-beta 1 was identified as a candidate regulatory PKC isoform.
引用
收藏
页码:G765 / G774
页数:10
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