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activation and cPKC-mediated cellular CFTR overexpression
Department of Integrative Biology, Pharmacology, and Physiology; and Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, The University of Texas Health Science Center at Houston, Medical School, Houston, Texas 77030
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: 
, 
1, and 2. cPKC-1 rises preceded and those of cPKC- and cPKC-2 paralleled cellular hyperproliferation and its effects on CFTR expression and
cAMP-dependent Cl current secretion. Only cPKC-1
and cPKC-2 were membrane translocated during TMCH. Furthermore, only
cPKC-1 trafficked to the nucleus, whereas cPKC-2 remained
partitioned among cytosolic, membrane, and cytoskeletal subcellular
fractions. Modest increases in novel PKC-
(nPKC-) expression and
subcellular membrane partitioning were recorded during TMCH, but no
changes were seen for PKC-
or -
. No nPKC isoform nuclear
partitioning was detected. The orally bioactive cPKC inhibitor
Ro-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-1 was identified as a candidate regulatory PKC isoform.
protein kinase C; cystic fibrosis transmembrane conductance regulator; anion transport; regulation; mouse
This article has been cited by other articles:
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  S. Umar, Y. Wang, A. P. Morris, and J. H. Sellin Dual alterations in casein kinase I-{epsilon} and GSK-3beta modulate beta-catenin stability in hyperproliferating colonic epithelia Am J Physiol Gastrointest Liver Physiol, February 1, 2007; 292(2): G599 - G607. [Abstract] [Full Text] [PDF]
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J. R. Broughman, L. Sun, S. Umar, J. Scott, J. H. Sellin, and A. P. Morris Chronic PKC-beta activation in HT-29 Cl.19a colonocytes prevents cAMP-mediated ion secretion by inhibiting apical membrane current generation Am J Physiol Gastrointest Liver Physiol, August 1, 2006; 291(2): G318 - G330. [Abstract] [Full Text] [PDF]
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J. R. Broughman, L. Sun, S. Umar, J. H. Sellin, and A. P. Morris Chronic PKC-beta2 activation in HT-29 Cl.19a colonocytes prevents cAMP-mediated ion secretion by inhibiting apical membrane CFTR targeting Am J Physiol Gastrointest Liver Physiol, August 1, 2006; 291(2): G331 - G344. [Abstract] [Full Text] [PDF]
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 J. H. Sellin, S. Umar, J. Xiao, and A. P. Morris Increased {beta}-Catenin Expression and Nuclear Translocation Accompany Cellular Hyperproliferation in Vivo Cancer Res., April 1, 2001; 61(7): 2899 - 2906. [Abstract] [Full Text]
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S. Umar, J. H. Sellin, and A. P. Morris Increased nuclear translocation of catalytically active PKC-zeta during mouse colonocyte hyperproliferation Am J Physiol Gastrointest Liver Physiol, July 1, 2000; 279(1): G223 - G237. [Abstract] [Full Text] [PDF]
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