Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2010

Open Access 01-12-2010 | Research

The promoter for intestinal cell kinase is head-to-head with F-Box 9 and contains functional sites for TCF7L2 and FOXA factors

Authors: Thomas W Sturgill, Paul B Stoddard, Steven M Cohn, Marty W Mayo

Published in: Molecular Cancer | Issue 1/2010

Login to get access

Abstract

Background

Intestinal cell kinase (ICK; GeneID 22858) is a conserved MAPK and CDK-like kinase that is widely expressed in human tissues. Data from the Cancer Genome Anatomy Project indicated ICK mRNA is increased in cancer, and that its expression correlated with expression of mRNA for an uncharacterized F-box protein, FBX9 (GeneID: 26268). ICK and FBX9 genes are arranged head-to-head on opposite strands, with start sites for transcription separated by ~3.3 kb. We hypothesized ICK and FBX9 are potentially important genes in cancer controlled by a bidirectional promoter.

Results

We assessed promoter activity of the intergenic region in both orientations in cancer cell lines derived from breast (AU565, SKBR3), colon (HCT-15, KM12), and stomach (AGS) cancers, as well as in embryonic human kidney (HEK293T) cells. The intergenic segment was active in both orientations in all of these lines, and ICK promoter activity was greater than FBX9 promoter activity. Results from deletions and truncations defined a minimal promoter for ICK, and revealed that repressors and enhancers differentially regulate ICK versus FBX9 promoter activity. The ICK promoter contains consensus motifs for several FOX-family transcription factors that align when mouse and human are compared using EMBOSS. FOXA1 and FOXA2 increase luciferase activity of a minimal promoter 10-20 fold in HEK293T cells. Consensus sites for TCF7L2 (TCF4) (Gene Id: 6934) are also present in both mouse and human. The expression of β-catenin increased activity of the minimal promoter ~10 fold. ICK reference mRNAs (NM_014920.3, NM_016513) are expressed in low copy number and increased in some breast cancers, using a ten base tag 5'-TCAACCTTAT-3' specific for both ICK transcripts.

Conclusion

ICK and FBX9 are divergently transcribed from a bidirectional promoter that is GC-rich and contains a CpG island. A minimal promoter for ICK contains functional sites for β-cateinin/TCF7L2 and FOXA. These data are consistent with functions that have been proposed for ICK in development and in proliferation or survival of some breast and colon cancers.
Appendix
Available only for authorised users
Literature
1.
Fu Z, Schroeder MJ, Shabanowitz J, Kaldis P, Togawa K, Rustgi AK, Hunt DF, Sturgill TW: Activation of a nuclear Cdc2-related kinase within a mitogen-activated protein kinase-like TDY motif by autophosphorylation and cyclin-dependent protein kinase-activating kinase. Mol Cell Biol. 2005, 25: 6047-6064. 10.1128/MCB.25.14.6047-6064.2005PubMedCentralCrossRefPubMed
2.
Abe S, Yagi T, Ishiyama S, Hiroe M, Marumo F, Ikawa Y: Molecular cloning of a novel serine/threonine kinase, MRK, possibly involved in cardiac development. Oncogene. 1995, 11: 2187-2195.PubMed
3.
Fu Z, Kim J, Vidrich A, Sturgill TW, Cohn SM: Intestinal Cell Kinase, a MAP Kinase-Related Kinase, Regulates Proliferation and G1 Cell Cycle Progression of Intestinal Epithelial Cells. Am J Physiol Gastrointest Liver Physiol. 2009,
4.
Togawa K, Yan YX, Inomoto T, Slaugenhaupt S, Rustgi AK: Intestinal cell kinase (ICK) localizes to the crypt region and requires a dual phosphorylation site found in map kinases. J Cell Physiol. 2000, 183: 129-139. 10.1002/(SICI)1097-4652(200004)183:1<129::AID-JCP15>3.0.CO;2-SCrossRefPubMed
5.
Wohlbold L, Larochelle S, Liao JC, Livshits G, Singer J, Shokat KM, Fisher RP: The cyclin-dependent kinase (CDK) family member PNQALRE/CCRK supports cell proliferation but has no intrinsic CDK-activating kinase (CAK) activity. Cell Cycle. 2006, 5: 546-554. 10.4161/cc.5.5.2541CrossRefPubMed
6.
Wu GQ, Xie D, Yang GF, Liao YJ, Mai SJ, Deng HX, Sze J, Guan XY, Zeng YX, Lin MC, Kung HF: Cell cycle-related kinase supports ovarian carcinoma cell proliferation via regulation of cyclin D1 and is a predictor of outcome in patients with ovarian carcinoma. Int J Cancer. 2009, 125: 2631-2642. 10.1002/ijc.24630CrossRefPubMed
7.
Ko HW, Norman RX, Tran J, Fuller KP, Fukuda M, Eggenschwiler JT: Broad-minded links cell cycle-related kinase to cilia assembly and hedgehog signal transduction. Dev Cell. 18: 237-247.
8.
Cardozo T, Pagano M: The SCF ubiquitin ligase: insights into a molecular machine. Nat Rev Mol Cell Biol. 2004, 5: 739-751. 10.1038/nrm1471CrossRefPubMed
9.
Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H: Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science. 1997, 275: 1784-1787. 10.1126/science.275.5307.1784CrossRefPubMed
10.
Lin SY, Xia W, Wang JC, Kwong KY, Spohn B, Wen Y, Pestell RG, Hung MC: Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci USA. 2000, 97: 4262-4266. 10.1073/pnas.060025397PubMedCentralCrossRefPubMed
11.
Bacus SS, Kiguchi K, Chin D, King CR, Huberman E: Differentiation of cultured human breast cancer cells (AU-565 and MCF-7) associated with loss of cell surface HER-2/neu antigen. Mol Carcinog. 1990, 3: 350-362. 10.1002/mc.2940030607CrossRefPubMed
12.
Roschke AV, Tonon G, Gehlhaus KS, McTyre N, Bussey KJ, Lababidi S, Scudiero DA, Weinstein JN, Kirsch IR: Karyotypic complexity of the NCI-60 drug-screening panel. Cancer Res. 2003, 63: 8634-8647.PubMed
13.
Graham FL, Smiley J, Russell WC, Nairn R: Characteristics of a human cell line transformed by DNA from human adenovirus type 5. The Journal of general virology. 1977, 36: 59-74. 10.1099/0022-1317-36-1-59CrossRefPubMed
14.
Perez-Sanchez C, Gomez-Ferreria MA, de La Fuente CA, Granadino B, Velasco G, Esteban-Gamboa A, Rey-Campos J: FHX, a novel fork head factor with a dual DNA binding specificity. J Biol Chem. 2000, 275: 12909-12916. 10.1074/jbc.275.17.12909CrossRefPubMed
15.
Tuteja G, Kaestner KH: Forkhead transcription factors II. Cell. 2007, 131: 192- 10.1016/j.cell.2007.09.016CrossRefPubMed
16.
Tuteja G, Kaestner KH: SnapShot: forkhead transcription factors I. Cell. 2007, 130: 1160- 10.1016/j.cell.2007.09.005CrossRefPubMed
17.
Overdier DG, Porcella A, Costa RH: The DNA-binding specificity of the hepatocyte nuclear factor 3/forkhead domain is influenced by amino-acid residues adjacent to the recognition helix. Mol Cell Biol. 1994, 14: 2755-2766.PubMedCentralCrossRefPubMed
18.
Granadino B, Arias-de-la-Fuente C, Perez-Sanchez C, Parraga M, Lopez-Fernandez LA, del Mazo J, Rey-Campos J: Fhx (Foxj2) expression is activated during spermatogenesis and very early in embryonic development. Mech Dev. 2000, 97: 157-160. 10.1016/S0925-4773(00)00410-XCrossRefPubMed
19.
Takahashi H, Sakuta H, Shintani T, Noda M: Functional mode of FoxD1/CBF2 for the establishment of temporal retinal specificity in the developing chick retina. Dev Biol. 2009, 331: 300-310. 10.1016/j.ydbio.2009.05.549CrossRefPubMed
20.
Cross SH, Charlton JA, Nan X, Bird AP: Purification of CpG islands using a methylated DNA binding column. Nat Genet. 1994, 6: 236-244. 10.1038/ng0394-236CrossRefPubMed
21.
Gaston K, Fried M: CpG methylation has differential effects on the binding of YY1 and ETS proteins to the bi-directional promoter of the Surf-1 and Surf-2 genes. Nucleic Acids Res. 1995, 23: 901-909. 10.1093/nar/23.6.901PubMedCentralCrossRefPubMed
22.
Bogdanovic O, Veenstra GJ: DNA methylation and methyl-CpG binding proteins: developmental requirements and function. Chromosoma. 2009, 118: 549-565. 10.1007/s00412-009-0221-9PubMedCentralCrossRefPubMed
23.
Farcas R, Schneider E, Frauenknecht K, Kondova I, Bontrop R, Bohl J, Navarro B, Metzler M, Zischler H, Zechner U: Differences in DNA methylation patterns and expression of the CCRK gene in human and nonhuman primate cortices. Mol Biol Evol. 2009, 26: 1379-1389. 10.1093/molbev/msp046CrossRefPubMed
24.
Wetering van de M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, Horn van der K, Batlle E, Coudreuse D, Haramis AP: The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell. 2002, 111: 241-250. 10.1016/S0092-8674(02)01014-0CrossRefPubMed
25.
Hatzis P, Flier van der LG, van Driel MA, Guryev V, Nielsen F, Denissov S, Nijman IJ, Koster J, Santo EE, Welboren W: Genome-wide pattern of TCF7L2/TCF4 chromatin occupancy in colorectal cancer cells. Mol Cell Biol. 2008, 28: 2732-2744. 10.1128/MCB.02175-07PubMedCentralCrossRefPubMed
26.
Uesaka T, Kageyama N: Cdx2 homeodomain protein regulates the expression of MOK, a member of the mitogen-activated protein kinase superfamily, in the intestinal epithelial cells. FEBS Lett. 2004, 573: 147-154. 10.1016/j.febslet.2004.07.070CrossRefPubMed
27.
Beland M, Pilon N, Houle M, Oh K, Sylvestre JR, Prinos P, Lohnes D: Cdx1 autoregulation is governed by a novel Cdx1-LEF1 transcription complex. Mol Cell Biol. 2004, 24: 5028-5038. 10.1128/MCB.24.11.5028-5038.2004PubMedCentralCrossRefPubMed
28.
Velculescu VE, Zhang L, Vogelstein B, Kinzler KW: Serial analysis of gene expression. Science. 1995, 270: 484-487. 10.1126/science.270.5235.484CrossRefPubMed
29.
Fu Z, Larson KA, Chitta RK, Parker SA, Turk BE, Lawrence MW, Kaldis P, Galaktionov K, Cohn SM, Shabanowitz J: Identification of Yin-Yang Regulators and a Phosphorylation Consensus for Male Germ Cell-Associated Kinase (MAK)-Related Kinase. Mol Cell Biol. 2006, 26: 8639-8654. 10.1128/MCB.00816-06PubMedCentralCrossRefPubMed
30.
Adachi N, Lieber MR: Bidirectional gene organization: a common architectural feature of the human genome. Cell. 2002, 109: 807-809. 10.1016/S0092-8674(02)00758-4CrossRefPubMed
31.
Jin J, Cardozo T, Lovering RC, Elledge SJ, Pagano M, Harper JW: Systematic analysis and nomenclature of mammalian F-box proteins. Genes Dev. 2004, 18: 2573-2580. 10.1101/gad.1255304PubMedCentralCrossRefPubMed
32.
Ho Y, Gruhler A, Heilbut A, Bader GD, Moore L, Adams SL, Millar A, Taylor P, Bennett K, Boutilier K: Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature. 2002, 415: 180-183. 10.1038/415180aCrossRefPubMed
33.
Vidrich A, Buzan JM, Cohn SM: Intestinal stem cells and mucosal gut development. Curr Opin Gastroenterol. 2003, 19: 583-590. 10.1097/00001574-200311000-00012CrossRefPubMed
34.
Ang SL, Wierda A, Wong D, Stevens KA, Cascio S, Rossant J, Zaret KS: The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins. Development. 1993, 119: 1301-1315.PubMed
35.
Gao N, White P, Kaestner KH: Establishment of intestinal identity and epithelial-mesenchymal signaling by Cdx2. Dev Cell. 2009, 16: 588-599. 10.1016/j.devcel.2009.02.010PubMedCentralCrossRefPubMed
36.
Lahiry P, Wang J, Robinson JF, Turowec JP, Litchfield DW, Lanktree MB, Gloor GB, Puffenberger EG, Strauss KA, Martens MB: A multiplex human syndrome implicates a key role for intestinal cell kinase in development of central nervous, skeletal, and endocrine systems. American journal of human genetics. 2009, 84: 134-147. 10.1016/j.ajhg.2008.12.017PubMedCentralCrossRefPubMed
37.
Shinkai Y, Satoh H, Takeda N, Fukuda M, Chiba E, Kato T, Kuramochi T, Araki Y: A testicular germ cell-associated serine-threonine kinase, MAK, is dispensable for sperm formation. Mol Cell Biol. 2002, 22: 3276-3280. 10.1128/MCB.22.10.3276-3280.2002PubMedCentralCrossRefPubMed
38.
Bengs F, Scholz A, Kuhn D, Wiese M: LmxMPK9, a mitogen-activated protein kinase homologue affects flagellar length in Leishmania mexicana. Mol Microbiol. 2005, 55: 1606-1615. 10.1111/j.1365-2958.2005.04498.xCrossRefPubMed
39.
Miyata Y, Nishida E: Distantly related cousins of MAP kinase: biochemical properties and possible physiological functions. Biochem Biophys Res Commun. 1999, 266: 291-295. 10.1006/bbrc.1999.1705CrossRefPubMed
40.
Schindler K, Winter E: Phosphorylation of Ime2 regulates meiotic progression in Saccharomyces cerevisiae. J Biol Chem. 2006, 281: 18307-18316. 10.1074/jbc.M602349200CrossRefPubMed
41.
Clifford DM, Marinco SM, Brush GS: The meiosis-specific protein kinase Ime2 directs phosphorylation of replication protein A. J Biol Chem. 2004, 279: 6163-6170. 10.1074/jbc.M306943200CrossRefPubMed
42.
Morita K, Saitoh M, Tobiume K, Matsuura H, Enomoto S, Nishitoh H, Ichijo H: Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress. Embo J. 2001, 20: 6028-6036. 10.1093/emboj/20.21.6028PubMedCentralCrossRefPubMed
43.
Urban G, Golden T, Aragon IV, Cowsert L, Cooper SR, Dean NM, Honkanen RE: Identification of a functional link for the p53 tumor suppressor protein in dexamethasone-induced growth suppression. J Biol Chem. 2003, 278: 9747-9753. 10.1074/jbc.M210993200CrossRefPubMed
44.
Wechsler T, Chen BP, Harper R, Morotomi-Yano K, Huang BC, Meek K, Cleaver JE, Chen DJ, Wabl M: DNA-PKcs function regulated specifically by protein phosphatase 5. Proc Natl Acad Sci USA. 2004, 101: 1247-1252. 10.1073/pnas.0307765100PubMedCentralCrossRefPubMed
45.
Zhang J, Bao S, Furumai R, Kucera KS, Ali A, Dean NM, Wang XF: Protein phosphatase 5 is required for ATR-mediated checkpoint activation. Mol Cell Biol. 2005, 25: 9910-9919. 10.1128/MCB.25.22.9910-9919.2005PubMedCentralCrossRefPubMed
46.
Thress K, Henzel W, Shillinglaw W, Kornbluth S: Scythe: a novel reaper-binding apoptotic regulator. Embo J. 1998, 17: 6135-6143. 10.1093/emboj/17.21.6135PubMedCentralCrossRefPubMed
47.
Desmots F, Russell HR, Michel D, McKinnon PJ: Scythe regulates apoptosis-inducing factor stability during endoplasmic reticulum stress-induced apoptosis. J Biol Chem. 2008, 283: 3264-3271. 10.1074/jbc.M706419200CrossRefPubMed
48.
Minami R, Shimada M, Yokosawa H, Kawahara H: Scythe regulates apoptosis through modulating ubiquitin-mediated proteolysis of the Xenopus elongation factor XEF1AO. Biochem J. 2007, 405: 495-501. 10.1042/BJ20061886PubMedCentralCrossRefPubMed
49.
Miyata Y, Nishida E: CK2 controls multiple protein kinases by phosphorylating a kinase-targeting molecular chaperone, Cdc37. Mol Cell Biol. 2004, 24: 4065-4074. 10.1128/MCB.24.9.4065-4074.2004PubMedCentralCrossRefPubMed
50.
Manchen ST, Hubberstey AV: Human Scythe contains a functional nuclear localization sequence and remains in the nucleus during staurosporine-induced apoptosis. Biochem Biophys Res Commun. 2001, 287: 1075-1082. 10.1006/bbrc.2001.5701CrossRefPubMed
51.
Tsukahara T, Kimura S, Ichimiya S, Torigoe T, Kawaguchi S, Wada T, Yamashita T, Sato N: Scythe/BAT3 regulates apoptotic cell death induced by papillomavirus binding factor in human osteosarcoma. Cancer Sci. 2009, 100: 47-53. 10.1111/j.1349-7006.2008.00991.xCrossRefPubMed
52.
Nguyen P, Bar-Sela G, Sun L, Bisht KS, Cui H, Kohn E, Feinberg AP, Gius D: BAT3 and SET1A form a complex with CTCFL/BORIS to modulate H3K4 histone dimethylation and gene expression. Mol Cell Biol. 2008, 28: 6720-6729. 10.1128/MCB.00568-08PubMedCentralCrossRefPubMed
53.
Wang R, Liew CC: The human BAT3 ortholog in rodents is predominantly and developmentally expressed in testis. Mol Cell Biochem. 1994, 136: 49-57. 10.1007/BF00931604CrossRefPubMed
54.
Jinno A, Tanaka K, Matsushime H, Haneji T, Shibuya M: Testis-specific mak protein kinase is expressed specifically in the meiotic phase in spermatogenesis and is associated with a 210-kilodalton cellular phosphoprotein. Mol Cell Biol. 1993, 13: 4146-4156.PubMedCentralCrossRefPubMed
55.
Hublitz P, Albert M, Peters AH: Mechanisms of transcriptional repression by histone lysine methylation. Int J Dev Biol. 2009, 53: 335-354. 10.1387/ijdb.082717phCrossRefPubMed
56.
Sasaki T, Gan EC, Wakeham A, Kornbluth S, Mak TW, Okada H: HLA-B-associated transcript 3 (Bat3)/Scythe is essential for p300-mediated acetylation of p53. Genes Dev. 2007, 21: 848-861. 10.1101/gad.1534107PubMedCentralCrossRefPubMed
57.
Wang Y, Broderick P, Webb E, Wu X, Vijayakrishnan J, Matakidou A, Qureshi M, Dong Q, Gu X, Chen WV: Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat Genet. 2008, 40: 1407-1409. 10.1038/ng.273PubMedCentralCrossRefPubMed
58.
Raychaudhuri P, Lau LF, Grayson D, Kaplan J: Robert H. Costa: 1957-2006. Hepatology. 2006, 44: 1364- 10.1002/hep.21410CrossRefPubMed
59.
Ye H, Kelly TF, Samadani U, Lim L, Rubio S, Overdier DG, Roebuck KA, Costa RH: Hepatocyte nuclear factor 3/fork head homolog 11 is expressed in proliferating epithelial and mesenchymal cells of embryonic and adult tissues. Mol Cell Biol. 1997, 17: 1626-1641.PubMedCentralCrossRefPubMed
60.
Mallo GV, Soubeyran P, Lissitzky JC, Andre F, Farnarier C, Marvaldi J, Dagorn JC, Iovanna JL: Expression of the Cdx1 and Cdx2 homeotic genes leads to reduced malignancy in colon cancer-derived cells. J Biol Chem. 1998, 273: 14030-14036. 10.1074/jbc.273.22.14030CrossRefPubMed
61.
Costa RH, Grayson DR: Site-directed mutagenesis of hepatocyte nuclear factor (HNF) binding sites in the mouse transthyretin (TTR) promoter reveal synergistic interactions with its enhancer region. Nucleic Acids Res. 1991, 19: 4139-4145. 10.1093/nar/19.15.4139PubMedCentralCrossRefPubMed
62.
Boulanger J, Vezina A, Mongrain S, Boudreau F, Perreault N, Auclair BA, Laine J, Asselin C, Rivard N: Cdk2-dependent phosphorylation of homeobox transcription factor CDX2 regulates its nuclear translocation and proteasome-mediated degradation in human intestinal epithelial cells. J Biol Chem. 2005, 280: 18095-18107. 10.1074/jbc.M502184200CrossRefPubMed
63.
Sandelin A, Wasserman W, Lenhard B: ConSite:web-based prediction of regulatory elements using cross-species comparison. Nucleic Acids Res. 2004, 32: W249-252. 10.1093/nar/gkh372PubMedCentralCrossRefPubMed
64.
Mayo MW, Denlinger CE, Broad RM, Yeung F, Reilly ET, Shi Y, Jones DR: Ineffectiveness of histone deacetylase inhibitors to induce apoptosis involves the transcriptional activation of NF-kappa B through the Akt pathway. J Biol Chem. 2003, 278: 18980-18989. 10.1074/jbc.M211695200CrossRefPubMed
Metadata
Title
The promoter for intestinal cell kinase is head-to-head with F-Box 9 and contains functional sites for TCF7L2 and FOXA factors
Authors
Thomas W Sturgill
Paul B Stoddard
Steven M Cohn
Marty W Mayo
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2010
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-9-104

Other articles of this Issue 1/2010

Molecular Cancer 1/2010 Go to the issue

Research

Differential requirement of the epidermal growth factor receptor for G protein-mediated activation of transcription factors by lysophosphatidic acid

Research

LIMD1 is more frequently altered than RB1 in head and neck squamous cell carcinoma: clinical and prognostic implications

Research

Retinoic acid protects human breast cancer cells against etoposide-induced apoptosis by NF-kappaB-dependent but cIAP2-independent mechanisms

Research

Constitutively overexpressed 21 kDa protein in Hodgkin lymphoma and aggressive non-Hodgkin lymphomas identified as cytochrome B5b (CYB5B)

Research

Complement activation mediates cetuximab inhibition of non-small cell lung cancer tumor growth in vivo

Research

Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits