The secreted glycoprotein CREG enhances differentiation of NTERA-2 human embryonal carcinoma cells.
Differentiation of the human embryonal carcinoma cell line NTERA-2 is characterized by changes in morphology, altered patterns of gene expression, reduced proliferative potential, and a loss of tumorigenicity. The cellular repressor of E1A-stimulated genes, CREG, was previously shown to antagonize transcriptional activation and cellular transformation by the Adenovirus E1A oncoprotein. These properties suggested that CREG may function to inhibit cell growth and/or promote differentiation. Here we show that CREG is a secreted glycoprotein which enhances differentiation of NTERA-2 cells. Northern blot analysis reveals that, although CREG mRNA is widely expressed in adult tissues, CREG mRNA is not significantly expressed in pluripotent mouse embryonic stem cells or NTERA-2 embryonal carcinoma cells. CREG mRNA is rapidly induced upon in vitro differentiation of both mouse embryonic stem cells and human NTERA-2 cells. We show that constitutive expression of CREG in NTERA-2 cells enhances neuronal differentiation upon treatment with retinoic acid. Media enriched in CREG was also found to promote NTERA-2 differentiation in the absence of an inducer such as retinoic acid. These studies suggest that secreted CREG protein participates in a signaling cascade important for differentiation of pluripotent stem cells such as those found in teratocarcinomas.
Veal
E
E
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Groisman
R
R
Eisenstein
M
M
Gill
G
G
D000818:Animals; D018236:Carcinoma, Embryonal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006031:Glycosylation; D006801:Humans; D051379:Mice; D011499:Protein Processing, Post-Translational; D011817:Rabbits; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C114068:CREG1 protein, human; C485248:Creg protein, mouse; D012097:Repressor Proteins; D014212:Tretinoin