Transforming Growth Factor-β Induces Platelet-Derived Growth Factor (PDGF) Messenger RNA and PDGF Secretion while Inhibiting Growth in Normal Human Mammary Epithelial Cells

Abstract

Platelet-derived growth factor (PDGF) is a potent mitogen in human serum which specifically stimulates the proliferation of mesenchymal cells. We have now examined normal human mammary epithelial cells (HMEC) derived from reduction mammaplasties and grown in a serum-free defined medium. Medium conditioned by HMEC contained a PDGF-like activity that competed with [125I]PDGF for binding to PDGF receptors in normal human fibroblasts. When conditioned media were incubated with antiserum specific for either PDGF-A or PDGF-B, only PDGF-A antiserum was capable of inhibiting binding of conditioned media to PDGF receptors. Using an RNase protection assay, mRNA from normal HMEC was probed for both the PDGF-A and PDGF-B chains. Little or no PDGF-B was found in HMEC strains, while a strong signal was seen with the PDGF-A probe. When HMEC were grown in the presence of transforming growth factor-beta (TGF beta) for 48 h, inhibition of growth was observed in association with a 20- to 40-fold stimulation of PDGF-B mRNA and a 2-fold stimulation of PDGF-A mRNA. This mRNA induction was extremely rapid (within 1 h), and secreted PDGF activity was induced 2- to 3-fold. Two other HMEC growth inhibitors and differentiating agents, sodium butyrate and phorbol ester 12-O-tetradecanoylphorbol-13-acetate, had no effect on PDGF mRNA regulation. The current study suggests that PDGF gene induction is an extremely rapid and specific indicator of TGF beta function regardless of whether TGF beta is acting in a growth stimulatory or inhibitory manner. Any role of PDGF-B in TGF beta modulation of differentiation of normal or malignant mammary gland remains to be determined.

Smad3 is required for dedifferentiation of retinal pigment epithelium following retinal detachment in mice

“…22,54 Our studies now show that TGF-b can induce synthesis and secretion of PDGF-BB and PDGF-AB in ARPE-19 cells, similar to its ability to induce synthesis of PDGF and activate PDGF receptors in a variety of other cells. 20,21,55 Importantly, this induction of PDGF by TGF-b has recently been demonstrated to be Smad3/4 dependent, 56 consistent with absence of PDGF-BB expression in the KO RPE cells postretinal detachment. The Smad3 dependence of PDGF-BB expression in vivo further suggests that its expression is dependent on TGF-b rather than a direct result of the injury.…”

“…[13][14][15][16] TGF-b2 is expressed at much higher levels than the other TGF-b isoforms in the vitreous humor 12,17 and is a likely mediator of EMT in RPE cells in vivo, although the specific signaling pathways involved have not been identified. 5,18,19 Moreover, PDGF, TGF-b1 and CTGF are each known to be targets of TGF-b2 signaling, [20][21][22][23] suggesting that TGFb2 could orchestrate the secondary effects of these other peptides on EMT and fibrosis in PVR.…”

Transforming growth factor‐β1 expression in Syrian hamster cheek pouch carcinogenesis

“…Since it has been reported that SCC cell lines are frequently refractory to TGF-p activity 1421. this protein has been implicated as a possible mediator of angiogenesis [25,26] and a modifier of tumoral stroma. At later stages of carcinogenesis, TGF-p may condition the corium for tumor invasion.…”

“…TGF-p types 1, 2, and 3 comprise a family of potential autocrine or paracrine growth-regulatory proteins of 25 kDa [16,231. Three TGF-p genes have been identified and characterized in mammals [241.…”

Platelet-derived Growth Factor Signaling and Human Cancer

“…However, subsequent studies revealed that PDGF is also produced by the epithelium, endothelium, and many other cell types which are in close apposition to mesenchymal cells, which express PDGF receptors. These expression patterns suggest PDGFmediated paracrine signaling (Ataliotis and Mercola, 1997;DiCorleto and Bowen-Pope, 1983;Bronzert et al, 1990).…”