Journal
ADVANCED DRUG DELIVERY REVIEWS
Volume 41, Issue 3, Pages 283-301Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/S0169-409X(00)00047-8
Keywords
protein kinase C; tight junction permeability; phorbol esters; bryostatin 1; epithelia
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Funding
- NCI NIH HHS [CA48121, CA67113] Funding Source: Medline
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The regulation of tight junction permeability by a variety of signal transduction pathways is summarized. An emphasis is placed on regulation of paracellular permeability by the protein kinase C family of isoforms, which involves the reporting of a large number of studies using the phorbol ester family of protein kinase C activators. The ability of protein kinase C activation to open epithelial barriers to a very wide range of solutes is emphasized, but then countered with discussion of the role of phorbol esters and protein kinase C activation in epithelial carcinogenesis. The ability of protein kinase C activation to enable growth factors to leak from luminal fluid compartments of epithelial tissues into lateral intercellular and interstitial fluid spaces may play a role in this carcinogenic action. An examination of protein kinase C effects on the phosphorylation states of tight junctional proteins suggests that downstream kinases and/or phosphatases mediate protein kinase C's effect on tight junction permeability. A role for protein kinase C in transepithelial drug delivery is questioned herein. The tight junctional leakiness associated with protein kinase C activation and apparently intrinsic to transformed epithelia suggests a potentially useful role for tight junction leakiness as a marker for early cancer diagnosis. (C) 2000 Elsevier Science B.V. All rights reserved.
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