P311 induces a TGF-beta1-independent, nonfibrogenic myofibroblast phenotype.
P311, also called PTZ17, was identified by suppressive subtraction hybridization as potentially involved in smooth muscle (SM) myogenesis. P311 is an 8-kDa protein with several PEST-like motifs found in neurons and muscle. P311 transfection into two fibroblast cell lines, NIH 3T3 and C3H10 T1/2, induced phenotypic changes consistent with myofibroblast transformation, including upregulation of SM alpha-actin and SM22, induction of FGF-2, VEGF, PDGF, and PDGF receptors, upregulation of integrins alpha3 and alpha5, and increased proliferation rate. The P311-mediated changes differed, however, from the well-characterized myofibroblast in that P311 inhibited TGF-beta1, TGF-beta receptor 2, and TGF-beta1-activating MMP-2 and MMP-9, with the resultant decrease in collagen 1 and 3 expression. The effect of P311 on collagen was overcome by exogenous TGF-beta1, indicating that the cells were responsive to TGF-beta1 paracrine stimulus. In support of a role for P311 in vivo, immunohistochemical examination of human wounds showed P311 only in myofibroblasts and their activated precursors. To our knowledge, these studies are the first to implicate P311 in myofibroblast transformation, to demonstrate that transformation may occur independently of TGF-beta1, and to suggest that P311 may prevent fibrosis.
Pan
Desi
D
Department of Pathology, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA.
Zhe
Xiaoning
X
Jakkaraju
Sandhya
S
Taylor
Gregory A
GA
Schuger
Lucia
L
D016475:3T3 Cells; D000818:Animals; D002454:Cell Differentiation; D003094:Collagen / Q000096:biosynthesis; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000502:physiology*; D015513:Oncogene Proteins / Q000502:physiology*; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D013718:Tensile Strength; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1
C428027:NREP protein, human; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D010982:Platelet-Derived Growth Factor; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen