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signaling in pancreatic acinar cells
Departments of 1 Physiology and 2 Surgery, University of Michigan Medical School, Ann Arbor, Michigan 48109
Transforming growth factor-
(TGF-) is a potent inhibitor
of pancreatic acinar cell growth. Smad4 is a central mediator in the
TGF- signaling pathway. To study the effect of Smad4 on pancreatic growth, cell cycle protein expression, and the expression of a TGF--responsive promoter in vitro, we constructed an adenovirus containing dominant-negative COOH terminal truncated Smad4 (AddnSmad4) downstream of the rat elastase promoter. Acinar cells expressed dominant-negative Smad4 within 8 h after infection, and expression persisted for 72 h. Mouse pancreatic acini were infected with either AddnSmad4 or control adenovirus expressing green fluorescent protein, and TGF- was added 8 h after infection. Acinar cells were then incubated for 1, 2, or 3 days, and
[3H]thymidine incorporation was determined. AddnSmad4
significantly reduced TGF- inhibition of [3H]thymidine
incorporation, with maximal effects on day 3. AddnSmad4 also
completely blocked TGF--mediated growth inhibition in the presence
of basic fibroblast growth factor. We next examined the effects of
AddnSmad4 on TGF--induced expression of the cell cycle regulatory
proteins p21Cip1 and p27Kip1. TGF- induced
upregulation of p21Cip1, which was completely blocked by
AddnSmad4. AddnSmad4 also inhibited TGF--induced expression of the
TGF--responsive luciferase reporter 3TP-Lux. These results show that
Smad4 is essential in TGF--mediated signaling in pancreatic acinar cells.
growth regulation; pancreas; cell cycle; Smad proteins
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