Transcriptional Regulation of the Human Carboxyl Ester Lipase Gene in Exocrine Pancreas

Lidberg, Ulf; Kannius-Janson, Marie; Nilsson, Jeanette; Bjursell, Gunnar

doi:10.1074/jbc.273.47.31417

Cited by 12 publications

(23 citation statements)

References 58 publications

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“…Cell Extracts and Reporter Gene Assays-HC11 cells, stably transfected with CEL promoter/luciferase constructs with an intact (mCEL1831Luc) or mutated (mCEL-1831NF1:1mutLuc) NF1-binding site (previously described (6)) were grown to different degrees of confluence and then harvested as described previously (21). Luciferase assays were performed using the Promega kit with 50 l of cell lysate and assayed in a luminometer (Berthold).…”

Section: Methodsmentioning

confidence: 99%

Nuclear Factor 1-C2 Contributes to the Tissue-specific Activation of a Milk Protein Gene in the Differentiating Mammary Gland

Kannius-Janson¹,

Johansson²,

Bjursell³

et al. 2002

Journal of Biological Chemistry

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Members of the nuclear factor 1 (NF1) transcription factor family have been postulated to be involved in the regulation of milk genes. In this work we have been able to identify the splice variant NF1-C2 as an important member of a tissue-specific activating complex that regulates the milk gene encoding carboxyl ester lipase (CEL). Mutation of the NF1-binding site in the CEL gene promoter results in a drastic reduction of the gene expression to about 15% in mammary epithelial cells. Furthermore, we demonstrate that the NF1-C2 protein interacts with a higher affinity to the NF1-binding site in the CEL gene promoter than other NF1 family members do and that NF1-C2 in the mouse mammary gland is a phosphorylated protein. During development of the mouse mammary gland, binding of NF1-C2 to the CEL gene promoter is induced at midpregnancy, in correlation with the induction of CEL gene expression. The fact that the NF1-C2 involving complex remains throughout the lactation period and decreases during the weaning period, when the CEL gene is down-regulated, supports its importance in the regulation of CEL gene expression. To our knowledge, this is the first report identifying a specific, endogenously expressed NF1 isoform to be involved in the tissue-specific activation of a gene.

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Section: Methodsmentioning

confidence: 99%

Nuclear Factor 1-C2 Contributes to the Tissue-specific Activation of a Milk Protein Gene in the Differentiating Mammary Gland

Kannius-Janson¹,

Johansson²,

Bjursell³

et al. 2002

Journal of Biological Chemistry

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“…The difference is due to the presence of an overlapping CCAAT/ enhancer-binding protein (C/EBP)-like binding motif in the human gene sequence that interferes with PTF-1 binding to the same site (41). High-level expression of the human CEL gene in the pancreas is achieved by another pancreas-specific enhancer element found in the 5 Ј -upstream sequence of the CEL gene (42).…”

Section: Gene Expressionmentioning

confidence: 99%

Carboxyl ester lipase

Hui

Howles

2002

Journal of Lipid Research

196

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Carboxyl ester lipase (CEL), previously named cholesterol esterase or bile salt-stimulated (or dependent) lipase, is a lipolytic enzyme capable of hydrolyzing cholesteryl esters, tri-, di-, and mono-acylglycerols, phospholipids, lysophospholipids, and ceramide. The active site catalytic triad of serine-histidine-aspartate is centrally located within the enzyme structure and is partially covered by a surface loop. The carboxyl terminus of the protein regulates enzymatic activity by forming hydrogen bonds with the surface loop to partially shield the active site. Bile salt binding to the loop domain frees the active site for accessibility by water-insoluble substrates. CEL is synthesized primarily in the pancreas and lactating mammary gland, but the enzyme is also expressed in liver, macrophages, and in the vessel wall. In the gastrointestinal tract, CEL serves as a compensatory protein to other lipolytic enzymes for complete digestion and absorption of lipid nutrients. Importantly, CEL also participates in chylomicron assembly and secretion, in a mechanism mediated through its ceramide hydrolytic activity. Cell culture studies suggest a role for CEL in lipoprotein metabolism and oxidized LDL-induced atherosclerosis. Thus, this enzyme, which has a wide substrate reactivity and diffuse anatomic distribution, may have multiple functions in lipid and lipoprotein metabolism, and atherosclerosis. Carboxyl ester lipase (CEL), previously named pancreatic cholesterol esterase and also known as bile salt-stimulated (or -dependent) lipase, is a nonspecific lipolytic enzyme capable of hydrolyzing cholesteryl esters, tri-, di-, and mono-acylglycerols, phospholipids, lysophospholipids, and ceramide (1-3). The hydrolysis of water-insoluble carboxyl esters with long chain fatty acyl groups by CEL requires its activation by bile salt. However, CEL hydrolysis of water-soluble substrates such as carboxyl esters with short chain fatty acids or lysophospholipids does not have an absolute dependence on bile salt activation. The CEL protein is synthesized primarily in the pancreatic acinar cells and lactating mammary glands of higher mammals. Small amounts of CEL are found in other tissues, particularly the liver, macrophages, endothelial cells, and eosinophils (4-10). Extensive research has been performed in recent years on the structure-function relationship of this protein as well as its physiological role in lipid metabolism. A significant body of work has also been devoted to studying CEL processing and transport in pancreatic acinar cells. The latter topic was reviewed recently (11) and will be discussed only briefly in this article when appropriate. This article will present an updated review on the structure-function studies of CEL as well as an in-depth discussion on the current understanding of its role in lipid metabolism. PROTEIN STRUCTURE-FUNCTION RELATIONSHIP Active siteThe nucleotide sequence of CEL from various species shows that it is a highly conserved protein belonging to the ␣ / ␤ hydrolase family. The carb...

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“…HC11 cells, stably transfected with carboxyl ester lipase (CEL) promoter-luciferase constructs with an intact (mCEL-1831Luc) or mutated (mCEL-1831NF1:1mutLuc) NF1 site (previously described in reference 17) were grown to different degrees of confluence and then harvested as described previously (19). Luciferase assays were performed using a Promega kit with 50 l of cell lysate, and results were assayed by use of a luminometer (Berthold, Pforzheim, Germany).…”

mentioning

confidence: 99%

Nuclear Jak2 and Transcription Factor NF1-C2: a Novel Mechanism of Prolactin Signaling in Mammary Epithelial Cells

Nilsson¹,

Bjursell²,

Kannius-Janson³

2006

Molecular and Cellular Biology

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The classical mechanism by which prolactin transduces its signal in mammary epithelial cells is by activation of cytosolic signal transducer and activator of transcription 5 (Stat5) via a plasma membrane-associated prolactin receptor-Janus kinase 2 (Jak2) complex. Here we describe an alternative pathway through which prolactin via Jak2 localized in the nucleus activates the transcription factor nuclear factor 1-C2 (NF1-C2). Previous reports have demonstrated a nuclear localization of Jak2, but the physiologic importance of nuclear Jak2 has not been clear. We demonstrate that nuclear Jak2 regulates the amount of active NF1-C2 through tyrosine phosphorylation and proteasomal degradation. Our data also demonstrate a link between prolactin and p53 as well as the milk gene carboxyl ester lipase through nuclear Jak2 and NF1-C2. Hence, we describe a novel pathway through which nuclear Jak2 is subject to regulation by prolactin in mammary epithelial cells.The mammary gland is a complex organ that undergoes development and differentiation under the control of a number of hormones and growth factors, their receptors, and transcription factors. The polypeptide hormone prolactin has an essential role both in the differentiation of the gland during pregnancy and in the regulation of milk protein gene expression (13). Prolactin receptor signaling can be mediated through several different signaling pathways (2, 4, 9, 10), the principal of which in mammary epithelial cells is that through the receptor-associated tyrosine kinase Janus kinase 2 (Jak2) (21). Binding of prolactin to its receptor activates Jak2, which phosphorylates the transcription factor signal transducer and activator of transcription 5 (Stat5). Phosphorylated Stat5 dimerizes, translocates to the nucleus, and binds to its response elements (35). Both Jak2 and Stat5 have been demonstrated to be essential for mammary gland development and milk protein gene expression (23,29). Apart from the Jak2-Stat5 pathway, the target genes and factors that mediate the action of prolactin in the mammary gland under normal conditions are poorly understood.One important mechanism regulating signal transduction is that through proteolysis (6, 11). The proteasome pathway in particular plays an important role in the degradation of a number of cellular proteins (26,31). Earlier studies have shown that proteasome inhibitors prolong the activity of the Jak-Stat signaling pathway by protecting tyrosine-phosphorylated Jak2 proteins from degradation (33, 38).We have previously identified the transcription factor nuclear factor 1-C2 (NF1-C2) as an important activator of milk genes as well as the p53 tumor suppressor gene in the mouse mammary gland during pregnancy (14,16). This activity indicates that NF1-C2 might participate both in the establishment of a functional gland and in the protection of the gland against tumorigenesis during proliferation. Further, using studies with mouse mammary epithelial NMuMG cells and mammary tissue from heterozygous prolactin receptor knockout mice as a b...

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Transcriptional Regulation of the Human Carboxyl Ester Lipase Gene in Exocrine Pancreas

Cited by 12 publications

References 58 publications

Nuclear Factor 1-C2 Contributes to the Tissue-specific Activation of a Milk Protein Gene in the Differentiating Mammary Gland

Nuclear Factor 1-C2 Contributes to the Tissue-specific Activation of a Milk Protein Gene in the Differentiating Mammary Gland

Carboxyl ester lipase

Nuclear Jak2 and Transcription Factor NF1-C2: a Novel Mechanism of Prolactin Signaling in Mammary Epithelial Cells

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