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Submitted on October 14, 2003
Accepted on June 4, 2004
is Mediated by Both Phosphatidylinositol-3 Kinase (PI3K) and MAPK Pathways in Mammary Epithelial Cells
Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick NJ 08901-8520
* To whom correspondence should be addressed. E-mail: cohick{at}aesop.rugters.edu.
IGF binding protein (IGFBP)-3 is an important regulator of mammary epithelial cell (MEC) growth and can enhance the ability of both IGF-I and epidermal growth factor (EGF) ligands such as TGF-
to stimulate MEC proliferation. Here we investigate the role of the PI3K and MAPK pathways in the regulation of IGFBP-3 expression by IGF-I and TGF- in bovine MEC. Both growth factors stimulated DNA synthesis, although IGF-I was the stronger mitogen. IGF-I and TGF- also stimulated IGFBP-3 mRNA and protein levels. TGF- stimulated rapid, transient activation of Akt that was maximal at 5 min and diminished by 15 min. In contrast, IGF-I-induced Akt activation was maximal between 15 and 90 min and was sustained for 6 h. While ERK 1/2 was maximally stimulated by TGF- between 5 and 15 min, IGF-I did not stimulate discernable activation of ERK 1/2. In addition, TGF- but not IGF-I induced rapid phosphorylation of Shc, while only IGF-I activated insulin receptor substrate (IRS)-1. Pretreatment with the PI3K inhibitor LY294002 or knockdown of p85 with small interfering RNA inhibited IGF-I or TGF--stimulated IGFBP-3 expression. Similarly, MEK1 inhibitors PD98059 and U0126 each abolished TGF--stimulated increases in IGFBP-3 mRNA levels. In contrast to TGF-, IGF-I retained the ability to partially increase IGFBP-3 mRNA levels in the presence of MEK1 inhibitors, indicating that IGF-I may activate alternative substrates of the PI3K pathway that are involved in IGFBP-3 regulation. In conclusion, stimulation of IGFBP-3 mRNA levels by mitogens is regulated through both the PI3K and MAPK pathways in bovine MEC.
•
gene expression •
PI3K •
MAPK
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