An Akt- and Fra-1-dependent pathway mediates platelet-derived growth factor-induced expression of thrombomodulin, a novel regulator of smooth muscle cell migration.
Overdistension of hollow organs evokes pathological changes characterized by smooth muscle remodeling. Mechanical stimuli induce smooth muscle cell (SMC) growth through acute activation of signaling cascades and by increased expression of soluble mitogens. Physical forces have also been implicated in ligand-independent activation of receptor tyrosine kinases, including the platelet-derived growth factor (PDGF) receptor, although the extent to which this occurs in intact tissue is unknown. Previously, we implicated Akt and activator protein-1 (AP-1) as mediators of growth and gene expression in SMC exposed to cyclic stretch or PDGF. Here we show that bladder wall distension leads to PDGFR activation and identify thrombomodulin (TM) as an Akt and AP-1 target in SMC. We demonstrate that TM, also induced by bladder stretch injury, is regulated at the transcriptional level by the AP-1 components c-jun and Fra1. Mutation of an AP-1 motif at -2010/-2004 abolished both AP-1 binding and PDGF responsiveness of the TM promoter. Fra1 silencing diminished PDGF-induced TM expression and SMC cell cycle transit. In contrast, TM knockdown did not affect cell growth but attenuated PDGF-stimulated SMC migration. Taken together, these results reveal new facets of TM regulation in SMC and provide the first demonstration of a role for endogenous TM in PDGF-induced cell migration. Moreover, TM induction on bladder injury suggests that it may be a biomarker for pathological smooth muscle remodeling.
Ramachandran
Aruna
A
Urological Diseases Research Center, John F. Enders Research Laboratories, Room 1077, Children's Hospital Boston, 300 Longwood Ave., Boston, MA 02115, USA.
Ranpura
Sandeep A
SA
Gong
Edward M
EM
Mulone
Michelle
M
Cannon
Glenn M
GM
Adam
Rosalyn M
RM
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D005786:Gene Expression Regulation; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism*; D001743:Urinary Bladder / Q000033:anatomy & histology; D000099169:Fos-Related Antigen 1
D010982:Platelet-Derived Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D016760:Proto-Oncogene Proteins c-fos; D017479:Receptors, Platelet-Derived Growth Factor; D018180:Thrombomodulin; D000099169:Fos-Related Antigen 1
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