TGF-β induces connexin43 gene expression in normal murine mammary gland epithelial cells via activation of p38 and PI3K/AKT signaling pathways
✍ Scribed by Charlotte Tacheau; Juliette Fontaine; Jennifer Loy; Alain Mauviel; Franck Verrecchia
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 398 KB
- Volume
- 217
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
One of the shared physiological roles between TGF‐β and connexin family members is to inhibit epithelial cell cycle progression and consequently, to provide protection against malignant transformation. Herein, we demonstrated that TGF‐β1 induces the expression of connexin43 (Cx43) in normal murine mammary gland (NMuMG) cell lines at the protein and mRNA levels, and transcriptionally. Using overexpression of a truncated dominant‐negative form of Cx43, we determined that the modulation of gap junctional communication by TGF‐β1 plays a key role in the control of NMuMG cells proliferation by TGF‐β1. In addition, using overexpression of truncated dominant‐negative forms of either Smad2 or Smad3, and MDA‐MB‐468 human breast carcinoma cells deficient for Smad4, we determined that the Smad cascade is not implicated in TGF‐β1 effect on Cx43 expression. Using specific pharmacologic inhibitors for JNK, ERK, p38, and PI3K/AKT signaling pathways, we demonstrated the cooperative role of p38 and PI3K/AKT signaling in TGF‐β1‐induced Cx43 expression and gap junctional communication. Furthermore, transfection of a c‐jun antisense expression vector significantly prevented TGF‐β1‐induced Cx43 gene expression demonstrating the involvement of c‐Jun/AP‐1 pathway together with p38 and PI3K/AKT pathways in mediating TGF‐β1‐induced Cx43 gene expression. J. Cell. Physiol. 217: 759–768, 2008. © 2008 Wiley‐Liss, Inc.