ANG II stimulates PKC-dependent ERK activation, DNA synthesis, and cell division in intestinal epithelial cells.
PKC, a major target for the tumor-promoting phorbol esters, has been implicated in the signal transduction pathways that mediate important functions in intestinal epithelial cells, including proliferation and carcinogenesis. With the use of IEC-18 cells arrested in G0/G1, addition of phorbol esters resulted in a modest increase in [3H]thymidine incorporation and a slight shift toward the S and G2/M phases of the cell cycle, whereas the combination of EGF and phorbol 12,13-dibutyrate (PDB) synergistically stimulated DNA synthesis. To investigate the effects of receptor-mediated PKC activation on mitogenesis, we demonstrated that ANG II induced ERK activation, a response completely blocked by pretreatment with mitogen/extracellular signal-regulated kinase inhibitors or specific PKC inhibitors. Furthermore, ANG II stimulated an over threefold increase in [3H]thymidine incorporation that was corroborated by flow cytometric analysis of the cell cycle to levels comparable to that achieved by the combination of EGF and PDB. Taken together, our results indicate that receptor-mediated PKC activation, as induced by ANG II, transduces mitogenic signals leading to DNA synthesis and cell proliferation in IEC-18 cells.
Chiu
Terence
T
Department of Medicine, School of Medicine, CURE: Digestive Diseases Research Center and Molecular Biology Institute, University of California-Los Angeles, Los Angeles, CA 90095-1786, USA.
Santiskulvong
Chintda
C
Rozengurt
Enrique
E
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D007413:Intestinal Mucosa / Q000166:cytology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000502:physiology; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D002273:Carcinogens; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D015240:Phorbol 12,13-Dibutyrate; D004247:DNA; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases