Activation of the Canonical -Catenin Pathway by Histamine* Received for publication, September 29, 2003 Published, JBC Papers in Press, October 16, 2003, DOI 10.1074/jbc.M310712200 Sander H. Diks‡, James C. Hardwick, Remco M. Diab, Marije M. van Santen, Henri H. Versteeg, Sander J. H. van Deventer, Dick J. Richel, and Maikel P. Peppelenbosch From the Laboratory for Experimental Internal Medicine, Academic Medical Center, Meibergdreef 9, The Netherlands Histamine signaling is a principal regulator in a vari- ety of pathophysiological processes including inflamma- tion, gastric acid secretion, neurotransmission, and tu- mor growth. We report that histamine stimulation causes transactivation of a T cell factor/-catenin-re- sponsive construct in HeLa cells and in the SW-480 colon cell line, whereas histamine did not effect transactiva- tion of a construct containing the mutated response con- struct FOP. On the protein level, histamine treatment increases phosphorylation of glycogen synthase kinase 3- in HeLa cells, murine macrophages, and DLD-1, HT- 29, and SW-480 colon cell lines. Furthermore, histamine also decreases the phosphorylated -catenin content in HeLa cells and murine macrophages. Finally, pharma- cological inhibitors of the histamine H1 receptor coun- teracted histamine-induced T cell factor/-catenin- responsive construct transactivation and the dephosphorylation of -catenin in HeLa cells and in macrophages. We conclude that the canonical -catenin pathway acts downstream of the histamine receptor H1 in a variety of cell types. The observation that inflam- matory molecules, like histamine, activate the -catenin pathway may provide a molecular explanation for a pos- sible link between inflammation and cancer. Histamine, a biogenic amine formed by decarboxylation of the amino acid L-histidine (1), is found in large quantities in different kinds of tissue, such as mast cell granules, although numerous other cell types are capable of histamine synthesis as well (2). Histamine controls a multitude of physiological func- tions by activating specific receptors on the target cells. Four types of receptors for histamine have already been described. These receptors are distinguished by their sensitivity to spe- cific pharmacological agonists and antagonists and are named H1–H4 receptors (3–5). In general, the H1 receptor is involved in inflammatory responses, mediating blood vessel and bron- chial constriction, vascular permeabilization, and the synthesis of other inflammatory agents (6, 7). The H2 receptor is involved in gastric acid secretion (8), and the H3 receptor is implicated in autoinhibition of histamine synthesis and release (9). The newly discovered H4 receptor has many similarities with the H3 receptor and is able to bind histamine and pyrilamine with high affinity, but tissue distribution is different from the H3 receptor (4). Although anti-histamines are among the most prescribed drugs in the western world, signal transduction and the molecular mechanisms by which histamine receptor acti- vation induces changes in gene transcription and expression remain largely unresolved. Several groups have reported that cAMP and Ca 2+ signaling is induced in different cell types upon histamine stimulation (10, 11). We decided to determine the transcriptional responses of HeLa cells upon histamine stimulation by using specific reporter constructs for different transcription factors. We did this by using a panel of different transcription factor-sensitive reporter constructs, and we observed a histamine-dependent activation of Myc, a target of -catenin signaling. The molecu- lar details of the activation of -catenin-dependent signal transduction are well investigated with respect to the canonical Wnt signaling pathway. Secreted Wnt glycoproteins bind to the frizzled receptor to activate Dishevelled. In turn, Disheveled phosphorylates and inhibits a complex containing glycogen synthase kinase 3- (GSK3-) 1 , axin, and adenomatous polyp- osis coli. When there is no Wnt signal, unphosphorylated GSK3- phosphorylates -catenin, leading to the ubiquitina- tion and degradation of -catenin by the proteasome (12). Thus, activation of the Wnt pathway inhibits phosphorylation and subsequent degradation of -catenin, allowing its nuclear transport and gene induction by means of binding to T cell factor (TCF) (13, 14). Histamine receptors are G protein-coupled receptors that are able to activate G q /G 11 similarly to the frizzled receptor (3, 15, 16), but a connection between histamine and the -catenin pathway has not yet been described. Activation of both hista- mine receptors and the TCF/LEF family are associated with the regulation of T cell development (17–20). In addition, it is widely accepted that the development of colon cancer requires activation of the TCF/LEF/-catenin pathway (21) and that anti-inflammatory drugs inhibit colon cancer development (22). Cooper et al. (23) proposed a link between cancer and inflam- mation in an animal colitis model. They reported a positive correlation between inflammation and cancer in their colitis model, and an early event in this process is the nuclear trans- location of -catenin. Histamine is well known for it pro-inflam- matory characteristics, and histamine antagonists have been reported to inhibit tumor growth in the colon (24 –27). Other studies have implicated histamine as a growth factor in a mammary carcinoma cell line (28), whereas the TCF/LEF/- catenin pathway is also implicated in the growth of these cells (29, 30). Thus, a role for the TCF/LEF/-catenin pathway downstream of histamine receptors would not be inconsistent with existing literature data. These considerations prompted us to include the TCF/LEF/-catenin pathway in a screen for * The work in this article was supported by Grant 902–26-211 from Netherlands Organization for Scientific Research, Grant UvA 1998 – 1855 from Dutch Cancer Society, and Grant 99.188 from Netherlands Heart Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ‡ To whom correspondence should be addressed: Laboratory for Ex- perimental Internal Medicine, G2-130, Academic Medical Center, Meibergdreef 9, NL-1105 AZ, The Netherlands. Tel.: 31-20-566-6034; Fax: 31-20-697-7192; E-mail: S.H.Diks@amc.uva.nl. 1 The abbreviations used are: GSK3-, glycogen synthase kinase 3-; TCF, T cell factor; LEF, lymphoid enhancer factor; SEAP, secreted alkaline phosphatase; SRE, serum responsive. THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 278, No. 52, Issue of December 26, pp. 52491–52496, 2003 © 2003 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A. This paper is available on line at http://www.jbc.org 52491 by guest on June 17, 2020 http://www.jbc.org/ Downloaded from