Opposing roles of nuclear receptor HNF4α isoforms in colitis and colitis-associated colon cancer

eLife

Volumn 5, Issue MAY2016, 2016, Pages

  Chellappa, Karthikeyani ^a,d   Deol, Poonamjot ^a   Evans, Jane R ^a   Vuong, Linh M ^a   Chen, Gang ^b   Briançon, Nadege ^c   Bolotin, Eugene ^a   Lytle, Christian ^b   Nair, Meera G ^b   Sladek, Frances M ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c HARVARD MEDICAL SCHOOL   (United States)

^d UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HEPATOCYTE NUCLEAR FACTOR 4ALPHA; RESISTIN; HEPATOCYTE NUCLEAR FACTOR 4; HNF4A PROTEIN, MOUSE; ISOPROTEIN;

ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CHROMATIN IMMUNOPRECIPITATION; COLITIS; COLON CANCER; COLON MUCOSA; CONTROLLED STUDY; ENZYME LINKED IMMUNOSORBENT ASSAY; GENE EXPRESSION PROFILING; HISTOLOGY; HUMAN; HUMAN CELL; IMMUNOBLOTTING; IMMUNOFLUORESCENCE; IMMUNOHISTOCHEMISTRY; MALE; MASS SPECTROMETRY; MICROARRAY ANALYSIS; MOUSE; NONHUMAN; NUCLEOTIDE SEQUENCE; POLYACRYLAMIDE GEL ELECTROPHORESIS; POLYMERASE CHAIN REACTION; SCORING SYSTEM; YOUNG ADULT; ANIMAL; COLON TUMOR; COMPLICATION; DISEASE MODEL; PATHOLOGY;

ANIMALS; COLITIS; COLONIC NEOPLASMS; DISEASE MODELS, ANIMAL; HEPATOCYTE NUCLEAR FACTOR 4; MICE; PROTEIN ISOFORMS;

EID: 84975321837     PISSN: None     EISSN: 2050084X     Source Type: Journal    
DOI: 10.7554/eLife.10903     Document Type: Article

References (77)

1. Ahn SH, Shah YM, Inoue J, Morimura K, Kim I, Yim S, Lambert G, Kurotani R, Nagashima K, Gonzalez FJ, Inoue Y. 2008. Hepatocyte nuclear factor 4alpha in the intestinal epithelial cells protects against inflammatory bowel disease. Inflammatory Bowel Diseases 14: 908-920. doi: 10.1002/ibd.20413
2. Anderson JM, Van Itallie CM. 2009. Physiology and function of the tight junction. Cold Spring Harbor Perspectives in Biology 1: a002584. doi: 10.1101/cshperspect.a002584
3. Artis D, Wang ML, Keilbaugh SA, He W, Brenes M, Swain GP, Knight PA, Donaldson DD, Lazar MA, Miller HR, Schad GA, Scott P, Wu GD. 2004. RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proceedings of the National Academy of Sciences of the United States of America 101: 13596-13600. doi: 10.1073/pnas.0404034101
4. Bajwa PJ, Lee JW, Straus DS, Lytle C. 2009. Activation of PPARgamma by rosiglitazone attenuates intestinal Cl-secretion. AJP 297: G82-G89. doi: 10.1152/ajpgi.90640.2008
5. Barrett JC, Lee JC, Lees CW, Prescott NJ, Anderson CA, Phillips A, Wesley E, Parnell K, Zhang H, Drummond H, Nimmo ER, Massey D, Blaszczyk K, Elliott T, Cotterill L, Dallal H, Lobo AJ, Mowat C, Sanderson JD, Jewell DP, et al. 2009. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nature Genetics 41: 1330-1334. doi: 10.1038/ng.483
6. Barrett KE, Keely SJ. 2000. Chloride secretion by the intestinal epithelium: Molecular basis and regulatory aspects. Annual Review of Physiology 62: 535-572. doi: 10.1146/annurev.physiol.62.1.535
7. Battle MA, Konopka G, Parviz F, Gaggl AL, Yang C, Sladek FM, Duncan SA. 2006. Hepatocyte nuclear factor 4alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. Proceedings of the National Academy of Sciences of the United States of America 103: 8419-8424. doi: 10.1073/pnas.0600246103
8. Bolotin E, Liao H, Ta TC, Yang C, Hwang-Verslues W, Evans JR, Jiang T, Sladek FM. 2010. Integrated approach for the identification of human hepatocyte nuclear factor 4alpha target genes using protein binding microarrays. Hepatology 51: 642-653. doi: 10.1002/hep.23357
9. Brandl K, Rutschmann S, Li X, Du X, Xiao N, Schnabl B, Brenner DA, Beutler B. 2009. Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response. Proceedings of the National Academy of Sciences of the United States of America 106: 3300-3305. doi: 10. 1073/pnas.0813036106
10. Briançon N, Weiss MC. 2006. In vivo role of the hnf4alpha AF-1 activation domain revealed by exon swapping. The EMBO Journal 25: 1253-1262. doi: 10.1038/sj.emboj.7601021
11. Cancer Genome Atlas Network. 2012. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487: 330-337. doi: 10.1038/nature11252
12. Cattin AL, Le Beyec J, Barreau F, Saint-Just S, Houllier A, Gonzalez FJ, Robine S, Pinçon-Raymond M, Cardot P, Lacasa M, Ribeiro A. 2009. Hepatocyte nuclear factor 4alpha, a key factor for homeostasis, cell architecture, and barrier function of the adult intestinal epithelium. Molecular and Cellular Biology 29: 6294-6308. doi: 10. 1128/MCB.00939-09
13. Chahar S, Gandhi V, Yu S, Desai K, Cowper-Sallari R, Kim Y, Perekatt AO, Kumar N, Thackray JK, Musolf A, Kumar N, Hoffman A, Londono D, Vazquez BN, Serrano L, Shin H, Lupien M, Gao N, Verzi MP. 2014. Chromatin profiling reveals regulatory network shifts and a protective role for hepatocyte nuclear factor 4a during colitis. Molecular and Cellular Biology 34: 3291-3304. doi: 10.1128/MCB.00349-14
14. Chang HR, Nam S, Kook MC, Kim KT, Liu X, Yao H, Jung HR, Lemos R, Seo HH, Park HS, Gim Y, Hong D, Huh I, Kim YW, Tan D, Liu CG, Powis G, Park T, Liang H, Kim YH. 2016. HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer. Gut 65: 19-32. doi: 10.1136/gutjnl-2014-307918
15. Chellappa K, Jankova L, Schnabl JM, Pan S, Brelivet Y, Fung CL, Chan C, Dent OF, Clarke SJ, Robertson GR, Sladek FM. 2012. Src tyrosine kinase phosphorylation of nuclear receptor hnf4α correlates with isoform-specific loss of hnf4α in human colon cancer. Proceedings of the National Academy of Sciences of the United States of America 109: 2302-2307. doi: 10.1073/pnas.1106799109
16. Daigo K, Kawamura T, Ohta Y, Ohashi R, Katayose S, Tanaka T, Aburatani H, Naito M, Kodama T, Ihara S, Hamakubo T. 2011. Proteomic analysis of native hepatocyte nuclear factor-4α (hnf4α) isoforms, phosphorylation status, and interactive cofactors. The Journal of Biological Chemistry 286: 674-686. doi: 10. 1074/jbc.M110.154732
17. Darsigny M, Babeu JP, Dupuis AA, Furth EE, Seidman EG, Lévy E, Verdu EF, Gendron FP, Boudreau F. 2009. Loss of hepatocyte-nuclear-factor-4alpha affects colonic ion transport and causes chronic inflammation resembling inflammatory bowel disease in mice. PloS One 4: e7609. doi: 10.1371/journal.pone.0007609
18. Darsigny M, Babeu JP, Seidman EG, Gendron FP, Levy E, Carrier J, Perreault N, Boudreau F. 2010. Hepatocyte nuclear factor-4alpha promotes gut neoplasia in mice and protects against the production of reactive oxygen species. Cancer Research 70: 9423-9433. doi: 10.1158/0008-5472.CAN-10-1697
19. Dean S, Tang JI, Seckl JR, Nyirenda MJ. 2010. Developmental and tissue-specific regulation of hepatocyte nuclear factor 4-alpha (hnf4-alpha) isoforms in rodents. Gene Expression 14: 337-344. doi: 10.3727/105221610X12717040569901
20. Deuschle U, Schüler J, Schulz A, Schlüter T, Kinzel O, Abel U, Kremoser C. 2012. FXR controls the tumor suppressor NDRG2 and FXR agonists reduce liver tumor growth and metastasis in an orthotopic mouse xenograft model. PloS One 7: e43044. doi: 10.1371/journal.pone.0043044
21. Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Röder M, Kokocinski F, Abdelhamid RF, Alioto T, et al. 2012. Landscape of transcription in human cells. Nature 489: 101-108. doi: 10.1038/nature11233
22. Drakakaki G, van de Ven W, Pan S, Miao Y, Wang J, Keinath NF, Weatherly B, Jiang L, Schumacher K, Hicks G, Raikhel N. 2012. Isolation and proteomic analysis of the SYP61 compartment reveal its role in exocytic trafficking in arabidopsis. Cell Research 22: 413-424. doi: 10.1038/cr.2011.129
23. Eeckhoute J, Moerman E, Bouckenooghe T, Lukoviak B, Pattou F, Formstecher P, Kerr-Conte J, Vandewalle B, Laine B. 2003. Hepatocyte nuclear factor 4 alpha isoforms originated from the P1 promoter are expressed in human pancreatic beta-cells and exhibit stronger transcriptional potentials than P2 promoter-driven isoforms. Endocrinology 144: 1686-1694. doi: 10.1210/en.2002-0024
24. Elbediwy A, Zihni C, Terry SJ, Clark P, Matter K, Balda MS. 2012. Epithelial junction formation requires confinement of cdc42 activity by a novel SH3BP1 complex. The Journal of Cell Biology 198: 677-693. doi: 10. 1083/jcb.201202094
25. Ellard S, Colclough K. 2006. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young. Human Mutation 27: 854-869. doi: 10.1002/humu.20357
26. Erger RA, Casale TB. 1998. Tumor necrosis factor alpha is necessary for granulocyte-macrophage-colony-stimulating-factor-induced eosinophil transendothelial migration. International Archives of Allergy and Immunology 115: 24-32. doi: 10.1159/000023826
27. Fang K, Bruce M, Pattillo CB, Zhang S, Stone R, Clifford J, Kevil CG. 2011. Temporal genomewide expression profiling of DSS colitis reveals novel inflammatory and angiogenesis genes similar to ulcerative colitis. Physiological Genomics 43: 43-56. doi: 10.1152/physiolgenomics.00138.2010
28. Farina F, Gaillard J, Guérin C, Couté Y, Sillibourne J, Blanchoin L, Théry M. 2016. The centrosome is an actin-organizing centre. Nature Cell Biology 18: 65-75. doi: 10.1038/ncb3285
29. Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, Lees CW, Balschun T, Lee J, Roberts R, Anderson CA, Bis JC, Bumpstead S, Ellinghaus D, Festen EM, Georges M, Green T, Haritunians T, Jostins L, Latiano A, et al. 2010. Genome-wide meta-analysis increases to 71 the number of confirmed crohn’s disease susceptibility loci. Nature Genetics 42: 1118-1125. doi: 10.1038/ng.717
30. Garrison WD, Battle MA, Yang C, Kaestner KH, Sladek FM, Duncan SA. 2006. Hepatocyte nuclear factor 4alpha is essential for embryonic development of the mouse colon. Gastroenterology 130: 1207-1220. doi: 10.1053/j. gastro.2006.01.003
31. Grill JI, Neumann J, Hiltwein F, Kolligs FT, Schneider MR. 2015. Intestinal e-cadherin deficiency aggravates dextran sodium sulfate-induced colitis. Digestive Diseases and Sciences 60: 895-902. doi: 10.1007/s10620-015-3551-x
32. Gupta RK, Gao N, Gorski RK, White P, Hardy OT, Rafiq K, Brestelli JE, Chen G, Stoeckert CJ, Kaestner KH. 2007. Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on hnf-4alpha. Genes & Development 21: 756-769. doi: 10.1101/gad.1535507
33. Gupta RK, Vatamaniuk MZ, Lee CS, Flaschen RC, Fulmer JT, Matschinsky FM, Duncan SA, Kaestner KH. 2005. The MODY1 gene hnf-4alpha regulates selected genes involved in insulin secretion. The Journal of Clinical Investigation 115: 1006-1015. doi: 10.1172/JCI200522365
34. Hatziapostolou M, Polytarchou C, Aggelidou E, Drakaki A, Poultsides GA, Jaeger SA, Ogata H, Karin M, Struhl K, Hadzopoulou-Cladaras M, Iliopoulos D. 2011. An hnf4α-mirna inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell 147: 1233-1247. doi: 10.1016/j.cell.2011.10.043
35. Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ. 2001. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Molecular and Cellular Biology 21: 1393-1403. doi: 10.1128/MCB.21.4.1393-1403.2001
36. He W, Wang ML, Jiang HQ, Steppan CM, Shin ME, Thurnheer MC, Cebra JJ, Lazar MA, Wu GD. 2003. Bacterial colonization leads to the colonic secretion of relmbeta/fizz2, a novel goblet cell-specific protein. Gastroenterology 125: 1388-1397. doi: 10.1016/j.gastro.2003.07.009
37. Hebert AS, Richards AL, Bailey DJ, Ulbrich A, Coughlin EE, Westphall MS, Coon JJ. 2014. The one hour yeast proteome. Molecular & Cellular Proteomics 13: 339-347. doi: 10.1074/mcp.M113.034769
38. Hirota CL, McKay DM. 2009. Loss of ca-mediated ion transport during colitis correlates with reduced ion transport responses to a ca-activated K channel opener. British Journal of Pharmacology 156: 1085-1097. doi: 10.1111/j.1476-5381.2009.00122.x
39. Hogan SP, Seidu L, Blanchard C, Groschwitz K, Mishra A, Karow ML, Ahrens R, Artis D, Murphy AJ, Valenzuela DM, Yancopoulos GD, Rothenberg ME. 2006. Resistin-like molecule beta regulates innate colonic function: Barrier integrity and inflammation susceptibility. The Journal of Allergy and Clinical Immunology 118: 257-268. doi: 10.1016/j.jaci.2006.04.039
40. Hong YH, Varanasi US, Yang W, Leff T. 2003. AMP-activated protein kinase regulates hnf4alpha transcriptional activity by inhibiting dimer formation and decreasing protein stability. The Journal of Biological Chemistry 278: 27495-27501. doi: 10.1074/jbc.M304112200
41. Huang J, Levitsky LL, Rhoads DB. 2009. Novel P2 promoter-derived hnf4alpha isoforms with different n-terminus generated by alternate exon insertion. Experimental Cell Research 315: 1200-1211. doi: 10.1016/j.yexcr.2009. 01.004
42. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Philip Schumm L, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, et al. 2012. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491: 119-124. doi: 10.1038/nature11582
43. Kaestner KH. 2010. Making the liver what it is: The many targets of the transcriptional regulator hnf4alpha. Hepatology 51: 376-377. doi: 10.1002/hep.23487
44. Kopanja D, Stoyanova T, Okur MN, Huang E, Bagchi S, Raychaudhuri P. 2009. Proliferation defects and genome instability in cells lacking cul4a. Oncogene 28: 2456-2465. doi: 10.1038/onc.2009.86
45. Liu Y, Su W, Thompson EA, Leitges M, Murray NR, Fields AP. 2004. Protein kinase cbetaii regulates its own expression in rat intestinal epithelial cells and the colonic epithelium in vivo. The Journal of Biological Chemistry 279: 45556-45563. doi: 10.1074/jbc.M407701200
46. Lorentz O, Duluc I, Arcangelis AD, Simon-Assmann P, Kedinger M, Freund JN. 1997. Key role of the cdx2 homeobox gene in extracellular matrix-mediated intestinal cell differentiation. The Journal of Cell Biology 139: 1553-1565. doi: 10.1083/jcb.139.6.1553
47. Lytle C, Tod TJ, Vo KT, Lee JW, Atkinson RD, Straus DS. 2005. The peroxisome proliferator-activated receptor gamma ligand rosiglitazone delays the onset of inflammatory bowel disease in mice with interleukin 10 deficiency. Inflammatory Bowel Diseases 11: 231-243. doi: 10.1097/01.MIB.0000160805.46235.eb
48. McDaniel N, Lytle C. 1999. Parietal cells express high levels of na-k-2cl cotransporter on migrating into the gastric gland neck. The American Journal of Physiology 276: G1273-1278.
49. McVay LD, Keilbaugh SA, Wong TM, Kierstein S, Shin ME, Lehrke M, Lefterova MI, Shifflett DE, Barnes SL, Cominelli F, Cohn SM, Hecht G, Lazar MA, Haczku A, Wu GD. 2006. Absence of bacterially induced relmbeta reduces injury in the dextran sodium sulfate model of colitis. The Journal of Clinical Investigation 116: 2914-2923. doi: 10.1172/JCI28121
50. Miura A, Yamagata K, Kakei M, Hatakeyama H, Takahashi N, Fukui K, Nammo T, Yoneda K, Inoue Y, Sladek FM, Magnuson MA, Kasai H, Miyagawa J, Gonzalez FJ, Shimomura I. 2006. Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulin secretion by pancreatic beta-cells. The Journal of Biological Chemistry 281: 5246-5257. doi: 10.1074/jbc.M507496200
51. Mohammed H, D’Santos C, Serandour AA, Ali HR, Brown GD, Atkins A, Rueda OM, Holmes KA, Theodorou V, Robinson JL, Zwart W, Saadi A, Ross-Innes CS, Chin SF, Menon S, Stingl J, Palmieri C, Caldas C, Carroll JS. 2013. Endogenous purification reveals GREB1 as a key estrogen receptor regulatory factor. Cell Reports 3: 342-349. doi: 10.1016/j.celrep.2013.01.010
52. Motoshima H, Goldstein BJ, Igata M, Araki E. 2006. AMPK and cell proliferation-ampk as a therapeutic target for atherosclerosis and cancer. The Journal of Physiology 574: 63-71. doi: 10.1113/jphysiol.2006.108324
53. Nakhei H, Lingott A, Lemm I, Ryffel GU. 1998. An alternative splice variant of the tissue specific transcription factor hnf4alpha predominates in undifferentiated murine cell types. Nucleic Acids Research 26: 497-504. doi: 10.1093/nar/26.2.497
54. Neufert C, Becker C, Neurath MF. 2007. An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression. Nature Protocols 2: 1998-2004. doi: 10.1038/nprot.2007. 279
55. Nowarski R, Jackson R, Gagliani N, de Zoete MR, Palm NW, Bailis W, Low JS, Harman CC, Graham M, Elinav E, Flavell RA. 2015. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163: 1444-1456. doi: 10. 1016/j.cell.2015.10.072
56. Odom DT. 2004. Control of pancreas and liver gene expression by HNF transcription factors. Science 303: 1378-1381. doi: 10.1126/science.1089769
57. Oshima T, Kawasaki T, Ohashi R, Hasegawa G, Jiang S, Umezu H, Aoyagi Y, Iwanari H, Tanaka T, Hamakubo T, Kodama T, Naito M. 2007. Downregulated P1 promoter-driven hepatocyte nuclear factor-4alpha expression in human colorectal carcinoma is a new prognostic factor against liver metastasis. Pathology International 57: 82-90. doi: 10.1111/j.1440-1827.2006.02061.x
58. Perše M, Cerar A. 2012. Dextran sodium sulphate colitis mouse model: Traps and tricks. Journal of Biomedicine & Biotechnology 2012: 718617. doi: 10.1155/2012/718617
59. Potten CS, Booth C, Pritchard DM. 1997. The intestinal epithelial stem cell: The mucosal governor. International Journal of Experimental Pathology 78: 219-243. doi: 10.1046/j.1365-2613.1997.280362.x
60. Reiter A, Walz C, Watmore A, Schoch C, Blau I, Schlegelberger B, Berger U, Telford N, Aruliah S, Yin JA, Vanstraelen D, Barker HF, Taylor PC, O’Driscoll A, Benedetti F, Rudolph C, Kolb HJ, Hochhaus A, Hehlmann R, Chase A, et al. 2005. The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2. Cancer Research 65: 2662-2667. doi: 10.1158/0008-5472.CAN-04-4263
61. Richards TC. 1977. Early changes in the dynamics of crypt cell populations in mouse colon following administration of 1,2-dimethylhydrazine. Cancer Research 37: 1680-1685.
62. Saandi T, Baraille F, Derbal-Wolfrom L, Cattin AL, Benahmed F, Martin E, Cardot P, Duclos B, Ribeiro A, Freund JN, Duluc I. 2013. Regulation of the tumor suppressor homeogene cdx2 by hnf4α in intestinal cancer. Oncogene 32: 3782-3788. doi: 10.1038/onc.2012.401
63. Schneider MR, Dahlhoff M, Horst D, Hirschi B, Trülzsch K, Müller-Höcker J, Vogelmann R, Allgäuer M, Gerhard M, Steininger S, Wolf E, Kolligs FT. 2010. A key role for e-cadherin in intestinal homeostasis and paneth cell maturation. PloS One 5: e14325. doi: 10.1371/journal.pone.0014325
64. Sladek FM, Zhong WM, Lai E, Darnell JE. 1990. Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes & Development 4: 2353-2365. doi: 10.1101/gad.4.12b.2353
65. Sturm A, Dignass AU. 2008. Epithelial restitution and wound healing in inflammatory bowel disease. World Journal of Gastroenterology 14: 348-353. doi: 10.3748/wjg.14.348
66. Suh E, Traber PG. 1996. An intestine-specific homeobox gene regulates proliferation and differentiation. Molecular and Cellular Biology 16: 619-625. doi: 10.1128/MCB.16.2.619
67. Tamura A, Kitano Y, Hata M, Katsuno T, Moriwaki K, Sasaki H, Hayashi H, Suzuki Y, Noda T, Furuse M, Tsukita S, Tsukita S. 2008. Megaintestine in claudin-15-deficient mice. Gastroenterology 134: 523-534. doi: 10.1053/j. gastro.2007.11.040
68. Tanaka T, Jiang S, Hotta H, Takano K, Iwanari H, Sumi K, Daigo K, Ohashi R, Sugai M, Ikegame C, Umezu H, Hirayama Y, Midorikawa Y, Hippo Y, Watanabe A, Uchiyama Y, Hasegawa G, Reid P, Aburatani H, Hamakubo T, et al. 2006. Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4alpha in the pathogenesis of human cancer. The Journal of Pathology 208: 662-672. doi: 10.1002/path.1928
69. Tessner TG, Cohn SM, Schloemann S, Stenson WF. 1998. Prostaglandins prevent decreased epithelial cell proliferation associated with dextran sodium sulfate injury in mice. Gastroenterology 115: 874-956. doi: 10. 1016/S0016-5085(98)70259-8
70. Tifft KE, Bradbury KA, Wilson KL. 2009. Tyrosine phosphorylation of nuclear-membrane protein emerin by src, abl and other kinases. Journal of Cell Science 122: 3780-3790. doi: 10.1242/jcs.048397
71. Vuong LM, Chellappa K, Dhahbi JM, Deans JR, Fang B, Bolotin E, Titova NV, Hoverter NP, Spindler SR, Waterman ML, Sladek FM. 2015. Differential effects of hepatocyte nuclear factor 4α isoforms on tumor growth and t-cell factor 4/AP-1 interactions in human colorectal cancer cells. Molecular and Cellular Biology 35: 3471-3490. doi: 10.1128/MCB.00030-15
72. Walesky C, Edwards G, Borude P, Gunewardena S, O’Neil M, Yoo B, Apte U. 2013a. Hepatocyte nuclear factor 4 alpha deletion promotes diethylnitrosamine-induced hepatocellular carcinoma in rodents. Hepatology 57: 2480-2490. doi: 10.1002/hep.26251
73. Walesky C, Gunewardena S, Terwilliger EF, Edwards G, Borude P, Apte U. 2013b. Hepatocyte-specific deletion of hepatocyte nuclear factor-4 in adult mice results in increased hepatocyte proliferation. AJP 304: G26-G37. doi: 10.1152/ajpgi.00064.2012
74. Wang ML, Shin ME, Knight PA, Artis D, Silberg DG, Suh E, Wu GD. 2005. Regulation of RELM/FIZZ isoform expression by Cdx2 in response to innate and adaptive immune stimulation in the intestine. American Journal of Physiology. Gastrointestinal and Liver Physiology 288: G1074-G1083. doi: 10.1152/ajpgi.00442.2004
75. Xin D, Hu L, Kong X. 2008. Alternative promoters influence alternative splicing at the genomic level. PloS One 3: e2377. doi: 10.1371/journal.pone.0002377
76. Zhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z, Chambers MC, Zimmerman LJ, Shaddox KF, Kim S, Davies SR, Wang S, Wang P, Kinsinger CR, Rivers RC, Rodriguez H, Townsend RR, Ellis MJC, Carr SA, Tabb DL, et al. 2014. Proteogenomic characterization of human colon and rectal cancer. Nature 513: 382-387. doi: 10.1038/nature13438
77. Zulato E, Bergamo F, De Paoli A, Griguolo G, Esposito G, De Salvo GL, Mescoli C, Rugge M, Nardin M, Di Grazia L, Lonardi S, Indraccolo S, Zagonel V. 2014. Prognostic significance of AMPK activation in advanced stage colorectal cancer treated with chemotherapy plus bevacizumab. British Journal of Cancer 111: 25-32. doi: 10.1038/bjc.2014.274