Role of signal transducer and activator of transcription 3 (STAT3) in stretch injury to bladder smooth muscle cells.
Excessive stretch of the bladder can lead to wall thickening including the growth of bladder smooth muscle cells (BSMC). Only three phospho-proteins (JNK, p38, and PI3K) have been previously shown to participate in stretch-induced BSMC growth. CD1 mouse bladders were hyper- or non-distended by our ex vivo bladder distention model and screened, by a commercial screening method, for phosphorylated signaling proteins. This uncovered a factor previously unexamined for its role in bladder stretch injury: signal transducer and activator of transcription 3 (STAT3). STAT3 was assessed for its role in mitogen- and stretch-induced BSMC proliferation. Proliferation was assessed by 3H-thymidine incorporation/cell counting in response to mitogenic stimulation or to stretch on silastic collagen or carboxyl-coated membranes. JAK2, upstream of STAT3, was inhibited by AG490 (2 microM). Ex vivo distention of bladders activated a discrete number of kinases, including two MAPK pathways (JNK and ERK2) and STAT3. STAT3 signaling was activated during hyperdistention of intact bladder and by stretch and mitogenic treatments of BSMC in vitro. JAK2/STAT3 inhibition by AG490 blocked mitogen- and stretch-induced BSMC proliferation. Thus, BSMC stretch responses may involve the recruitment of both growth factor and mechanically induced BSMC growth responses integrated by a common signaling pathway, STAT3.
Halachmi
Sarel
S
Institute of Medical Sciences, The Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Aitken
Karen J
KJ
Szybowska
Marta
M
Sabha
Nesrin
N
Dessouki
Shariff
S
Lorenzo
Armando
A
Tse
Derrick
D
Bagli
Darius J
DJ
D000818:Animals; D049109:Cell Proliferation; D004791:Enzyme Inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects; D020935:MAP Kinase Signaling System; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology; D001743:Urinary Bladder / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology
D004791:Enzyme Inhibitors; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide