title: MUC1 expression is repressed by protein inhibitor of activated signal transducer and activator of transcription-y.
abstract: Mucin 1 (MUC1) is a transmembrane glycoprotein that modulates the interaction between the embryo and the uterine epithelial cell surface. MUC1 also is a tumor marker and has been implicated in the protection of cancer cells from immune cell attack as well as in cell signaling in some tumors. We and others have shown that MUC1 expression is activated by progesterone (P), TNF-alpha, and interferon-gamma (IFN-gamma). Here we demonstrate that MUC1 expression is down-regulated by overexpression of members of the protein inhibitor of activated signal transducer and activator of transcription (PIAS) family, PIAS1, PIAS3, PIASxalpha, PIASxbeta, and PIASy, in human uterine epithelial cell lines HES and HEC-1A and in a breast cancer cell line, T47D. Treatments with P, TNF-alpha, and IFN-gamma were unable to overcome the repression by PIASy. PIASy repression of basal, P-, and TNF-alpha-stimulated MUC1 promoter activity was not dependent on the PIASy sumoylation domain. In contrast, PIASy suppression of IFN-gamma-activated MUC1 promoter activity was dependent on the PIASy sumoylation domain. PIASy and P receptor B were localized to the nucleus upon P treatment, and small interfering RNA knockdown of PIASy resulted in an increase in P-mediated stimulation of MUC1 protein expression. Overexpression of PIASy did not affect P receptor B binding to the MUC1 promoter but surprisingly led to a loss of nuclear receptor corepressor (NCoR), which was recruited to the promoter in response to P. Collectively, these data indicate that PIASy may be a useful target for down-regulation of MUC1 expression in various contexts.
authors: Department of Reproductive Medicine, University of California, San Diego, School of Medicine, La Jolla, California 92093, USA.
authors: Melissa Jo
authors: MJ
authors: Brayman
authors: Neeraja
authors: N
authors: Dharmaraj
authors: Errin
authors: E
authors: Lagow
authors: Daniel D
authors: DD
authors: Carson
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004717:Endometrium / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008024:Ligands; D018396:Mucin-1 / Q000096:biosynthesis* / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D011374:Progesterone / Q000378:metabolism; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014599:Uterus / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D008024:Ligands; C060192:MUC1 protein, human; D018396:Mucin-1; C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D014409:Tumor Necrosis Factor-alpha; D011374:Progesterone; D007371:Interferon-gamma