The CrebA/Creb3-like transcription factors are major and direct regulators of secretory capacity

Department of Cell Biology, The Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
The Journal of Cell Biology (Impact Factor: 9.69). 11/2010; 191(3):479-92. DOI: 10.1083/jcb.201004062
Source: PubMed

ABSTRACT Secretion occurs in all cells, with relatively low levels in most cells and extremely high levels in specialized secretory cells, such as those of the pancreas, salivary, and mammary glands. How secretory capacity is selectively up-regulated in specialized secretory cells is unknown. Here, we find that the CrebA/Creb3-like family of bZip transcription factors functions to up-regulate expression of both the general protein machinery required in all cells for secretion and of cell type-specific secreted proteins. Drosophila CrebA directly binds the enhancers of secretory pathway genes and is both necessary and sufficient to activate expression of every secretory pathway component gene examined thus far. Microarray profiling reveals that CrebA also up-regulates expression of genes encoding cell type-specific secreted components. Finally, we found that the human CrebA orthologues, Creb3L1 and Creb3L2, have the ability to up-regulate the secretory pathway in nonsecretory cell types.

Download full-text


Available from: Rebecca M Fox, Jan 24, 2014
  • Source
    • "Even though sequence analyses of a number of 5′-flanking regions of Rab1b-mod- ulated genes indicate that the CREB consensus site was present in many of them, we cannot assume that the mechanism described above is controlling the expression of all the genes identified by our microarray analysis. Interestingly, the CREB-binding motif on the GM130 and KDELR promoters is similar to the CrebA binding site confirmed to be functional in a variety of secretory pathway genes in Drosophila (Fox et al., 2010). Because the CREB-like proteins Creb3L1 and Creb3L2 are the closest mammalian orthologues to Drosophila CrebA, we cannot rule out that other transcription factors, such as a CREB-like protein, could interact with the CREB consensus binding site on the GM130 or KDELR promoter regions. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rab1b belongs to the Rab-GTPase family that regulates membrane trafficking and signal transduction systems able to control diverse cellular activities including gene expression. Rab1b is essential for ER-Golgi transport. Although it is ubiquitously expressed, its mRNA levels vary among different tissues. This work aims to characterize the role of the high Rab1b levels detected in some secretory tissues. We report that, in HeLa cells, an increase in Rab1b levels induces changes in Golgi size and gene expression. Significantly, analyses applied to selected genes, KDELR3, GM130 (involved in membrane transport) and the proto-oncogene JUN, indicate that the Rab1b increase acts as a molecular switch to control their expression at the transcriptional level, resulting in changes at the protein level. These Rab1b-dependent changes require the activity of p38 MAPK and the CREB consensus binding site in those target promoter regions. Moreover, our results reveal that, in a secretory thyroid cell line (FRTL5), Rab1b expression increases in response to thyroid-stimulating hormone (TSH). Additionally, changes in Rab1b expression in FRTL5 cells modify the specific TSH-response. Our results show, for the first time, that changes in Rab1b levels modulate gene transcription and strongly suggest that a Rab1b increase is required to elicit a secretory response.
    Molecular biology of the cell 01/2013; 24(5). DOI:10.1091/mbc.E12-07-0530 · 5.98 Impact Factor
  • Source
    • "Somewhat surprisingly, this decline in myocardin is only transient (see Fig. 7A), and is not sufficient to elicit any significant decrease in the gene expression of its direct targets ACTA2 (encoding αSMA), CNN1 (encoding calponin 1) and TAGLN (transgelin) (see below). The genes CREB3L1 and CREB3L2 encode transcription factors recently demonstrated to control the expression of multiple components of the secretory pathway (Fox et al., 2010). Two genes (SCG2 and SEC14L1) encoding secretory pathway components are also present among the downregulated genes in our data, supporting the hypothesis that TGF-β signaling stimulates secretory function in general in myofibroblasts. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The myofibroblast is a mesenchymal cell characterized by synthesis of the extracellular matrix, plus contractile and secretory activities. Myofibroblasts participate in physiological tissue repair, but can also cause devastating fibrosis. They are present in the tumor stroma of carcinomas and contribute to tumor growth and spreading. As myofibroblasts derive from various cell types and appear in a variety of tissues, there is marked variability in their phenotype. As regulatory mechanisms of wound healing are likely conserved among vertebrates, detailed knowledge of these mechanisms in more distant species will help to distinguish general from specific phenomena. To provide this as yet missing comparison, we analyzed the impact of the chemical inhibition of TGF-beta signaling on gene expression in chicken embryo dermal myofibroblasts. We revealed genes previously reported in mammalian systems (e.g. SPON2, ASPN, COMP, LUM, HAS2, IL6, CXCL12, VEGFA) as well as novel TGF-beta dependent genes, among them PGF, VEGFC, PTN, FAM180A, FIBIN, ZIC1, ADCY2, RET, HHIP and DNER. Inhibition of TGF-beta signaling also induced multiple genes, including NPR3, AGTR2, MTUS1, SOD3 and NOV. We also analyzed the effects of long term inhibition, and found that it is not able to induce myofibroblast dedifferentiation.
    Gene 11/2012; 513(1). DOI:10.1016/j.gene.2012.10.069 · 2.08 Impact Factor
  • Source
    • "Considering that CREB3L1 is proteolytically activated in virus-infected cells, the protein may play an important role in preventing virusinduced tumorigenesis. Notably, the ability of CREB3L1 to inhibit cell proliferation has not been observed in previous studies that analyze genes activated by the protein (Kondo et al., 2005; Murakami et al., 2009; Vellanki et al., 2010; Fox et al., 2010). Unlike the current study, these analyses were not performed in virus-infected cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: CREB3L1/OASIS is a cellular transcription factor synthesized as a membrane-bound precursor and activated by regulated intramembrane proteolysis in response to stimuli like ER stress. Comparing gene expression between Huh7 subclones that are permissive for hepatitis C virus (HCV) replication versus the nonpermissive parental Huh7 cells, we identified CREB3L1 as a host factor that inhibits proliferation of virus-infected cells. Upon infection with diverse DNA and RNA viruses, including murine γ-herpesvirus 68, HCV, West Nile virus (WNV), and Sendai virus, CREB3L1 was proteolytically cleaved, allowing its NH(2) terminus to enter the nucleus and induce multiple genes encoding inhibitors of the cell cycle to block cell proliferation. Consistent with this, we observed a necessity for CREB3L1 expression to be silenced in proliferating cells that harbor replicons of HCV or WNV. Our results indicate that CREB3L1 may play an important role in limiting virus spread by inhibiting proliferation of virus-infected cells.
    Cell host & microbe 07/2011; 10(1):65-74. DOI:10.1016/j.chom.2011.06.006 · 12.19 Impact Factor
Show more