Sialomucin Complex (Rat Muc4) Is Regulated by Transforming Growth Factor β in Mammary Gland by a Novel Post-translational Mechanism

Abstract

Sialomucin complex (SMC, rat Muc4) is a heterodimeric glycoprotein complex consisting of a mucin subunit ASGP-1 (for ascites sialoglycoprotein-1) and a transmembrane subunit ASGP-2, produced from a single gene and precursor. SMC expression is tightly regulated in mammary gland; the level in lactating mammary gland is about 100-fold that in virgin gland. In rat mammary epithelial cells, SMC is post-transcriptionally regulated by Matrigel by inhibition of SMC precursor synthesis. SMC is also posttranscriptionally regulated by transforming growth factor-␤ (TGF␤). The repression of SMC expression by TGF␤ is rapid, is independent of TGF␤-induced cell cycle arrest, and does not require new protein synthesis. Unlike Matrigel, TGF␤ does not reduce SMC protein synthesis, as SMC precursor accumulation is equivalent in TGF␤-treated and untreated cells. Instead, SMC precursor in TGF␤-treated cells is more persistent and does not become processed as rapidly into mature ASGP-1 and ASGP-2, indicating that TGF␤ disrupts processing of SMC precursor. These results indicate that SMC, a product of normal mammary gland and milk, is regulated by TGF␤ by a novel post-translational mechanism. Thus, SMC is regulated by multiple posttranscriptional mechanisms, which serve to repress potential deleterious effects of overexpression.

SMAD2 and SMAD7 Involvement in the Post-translational Regulation of Muc4 via the Transforming Growth Factor-β and Interferon-γ Pathways in Rat Mammary Epithelial Cells

“…When SMAD2 expression was not blocked (sense and scrambled S-oligo), TGF-␤ suppressed Muc4/SMC expression. These data support the requirement for SMAD2 activation in regulating Muc4/SMC expression via the TGF-␤-SMAD pathway (11).…”

“…A major factor involved in this regulation appears to be TGF-␤ (10, 11), which inhibits Muc4/SMC expression by blocking processing of the Muc4/SMC precursor to its two subunits (11). Interestingly, this inhibitory effect of TGF-␤ on Muc4/SMC expression is lost in rat mammary adenocarcinoma cells (10), consistent with the loss of TGF-␤ responsiveness in many human breast cancers (12).…”

“…Muc4/SMC is developmentally regulated in the rat mammary gland, dramatically increasing its levels of expression in the lactating mammary gland compared with the virgin mammary gland, while decreasing again during mammary gland involution (10,11). Deviation from this regulatory mechanism can have adverse effects on the mammary gland, possibly propagating a cascade of deleterious events leading to neoplasia and tumor progression.…”

“…sion-Muc4/SMC has previously been shown to be regulated by TGF-␤ post-translationally (10,11). The aim of the current study was to define the mechanism previously postulated for post-translational regulation of Muc4/SMC.…”

Extracellular regulated kinase (ERK)-dependent regulation of sialomucin complex/rat Muc4 in mammary epithelial cells

“…Upon removal from virgin rat, epithelial cells of mammary glands in culture produce SMC/Muc4, which suggests mammary epithelial cells of virgin rats have the potential to make SMC/Muc4 but their in vivo microenvironment prevents them from doing so. In support of this proposal, the reconstituted basement membrane Matrigel and transforming growth factor-b (TGFb) are able to negatively regulate expression of SMC/Muc4 in vitro by post-transcriptional mechanisms (Price-Schiavi et al, 1998, 2000b.…”