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Effect of interferon-γ (IFN-γ) on transforming growth factor-β (TGF-β) regulation of sialomucin complex/Muc4

Sialomucin complex (SMC, rat Muc4) is a heterodimeric glycoprotein complex consisting of a mucin subunit ASGP-1 (Ascites sialoglycoprotein-1) and a transmembrane subunit ASGP-2, which is highly overexpressed on the surface of ascites 13762 rat mammary adenocarcinoma cells. The complex is produced from a single gene and polypeptide precursor. SMC is developmentally regulated in normal rat mammary gland by multiple and complex mechanisms, with levels in the lactating gland being 100-fold those in the virgin gland. SMC transcript levels are enhanced in normal rat mammary epithelial cells by fetal bovine serum, insulin, and IGF-1 by an ERK-1/2-dependent pathway. SMC is post-transcriptionally regulated by Matrigel (extracellular matrix) by inhibition of SMC precursor synthesis. SMC is also post-transcriptionally regulated by TGF-β by disruption of SMC precursor processing into mature ASGP-1 and ASGP-2. The inhibition of SMC levels by TGF-β occurs by an ERK1/2-independent pathway, suggesting that the SMAD or another pathway may be involved in this effect. Interestingly, the inhibition of SMC levels by TGF-β can be blocked by treatment with IFN-γ, which has been shown to block TGF-β effects via a Jak/Stat-dependent pathway. This effect is dose-responsive and is dependent on the order in which the cytokines are added, suggesting that the balance of signaling inputs is important in determining the expression level of SMC. Thus, SMC is regulated by multiple mechanisms, and the delicate interplay of the pathways involved serves to maintain normal levels of the complex and repress potential deleterious effects of overexpression.

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Price-Schiavi, S., Ramsauer, V., Zhu, X. et al. Effect of interferon-γ (IFN-γ) on transforming growth factor-β (TGF-β) regulation of sialomucin complex/Muc4. Breast Cancer Res 3 (Suppl 1), A48 (2001).

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