P311 induces a TGF-β1–independent, nonfibrogenic myofibroblast phenotype

Abstract

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 α−actin and SM22, induction of FGF-2, VEGF, PDGF, and PDGF receptors, upregulation of integrins α3 and α5, and increased proliferation rate. The P311-mediated changes differed, however, from the well-characterized myofibroblast in that P311 inhibited TGF-β1, TGF-β receptor 2, and TGF-β1-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-β1, indicating that the cells were responsive to TGF-β1 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-β1, and to suggest that P311 may prevent fibrosis.

Effect of Protein Kinase C delta (PKC-δ) Inhibition on the Transcriptome of Normal and Systemic Sclerosis Human Dermal Fibroblasts In Vitro

“…Thus, these genes represent novel or less well recognized participants in the fibrotic process that were upregulated by PKC-δ. The profibrogenic genes that were downregulated by PKC-δ inhibition ( Figure 4 ), which were confirmed by RT-PCR, included c5orf13, which downregulates TGF-β1 and TGF-βR2 and has been shown to decrease collagen expression and induce differentiation of myofibroblasts to fibroblasts [35]; CXCL6, a chemokine that displays increased expression during progression of liver fibrosis [36]; CXCL12, a chemokine that is a powerful attractant for fibrocytes and that participates in the angiogenesis associated with chronic inflammation and fibrosis and has been found to be increased in pulmonary fibrosis tissues [37]–[39]; GBP1, an interferon inducible guanylate binding protein that is expressed at gap junctions and is involved in endothelial cell proliferation and invasion [40]; SOX9, which is coexpressed with Col2a1, the gene encoding type II collagen, the major cartilage matrix protein [41] and which has recently been suggested to participate in SSc fibrosis [42]; and TNFRSF19, which is expressed primarily in prostate cells and is capable of activating the JNK pathway and of inducing NFκB activation [43].…”

P311 induces the transdifferentiation of epidermal stem cells to myofibroblast-like cells by stimulating transforming growth factor β1 expression

“…Because myofibroblasts are defined as specialized fibroblasts with smooth muscle-like features, we hypothesized that P311 might also be involved in myofibroblast formation. In fact, our and other studies have shown that P311 can induce primary human fibroblasts [20] and fibroblast cell lines [19, 21] to differentiate into myofibroblasts. We recently found that P311 was highly expressed in EpSCs that are located in the neo-epidermis and hair follicles during wound healing [22] and that P311 promoted EpSC migration.…”

“…The high level of expression of P311 in these tissues suggested that it plays an important role in wound healing and scar formation. P311 is a novel gene that encodes an 8-kDa protein which contains several PEST (rich in proline (P), glutamic acid (D), aspartic acid (E), and serine (S) or threonine (T))-like domains and participates in the development of neurons and smooth muscles [19]. Because myofibroblasts are defined as specialized fibroblasts with smooth muscle-like features, we hypothesized that P311 might also be involved in myofibroblast formation.…”

Transcriptome of Cultured Lung Fibroblasts in Idiopathic Pulmonary Fibrosis: Meta-Analysis of Publically Available Microarray Datasets Reveals Repression of Inflammation and Immunity Pathways

“…Double inactivation of LIMS1 and 2 leads to the development of heart failure and fibrosis in mice [11]. NREP regulates the TGF-β signaling pathway, and overexpression of NREP in fibroblasts suffices to induce proliferation and myofibroblastic transformation [12]. NREP is upregulated in hypertrophic skin scars [19], suggesting that this protein may be important for fibrogenesis in vivo.…”