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
BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

WD-repeat protein WDR13 is a novel transcriptional regulator of c-Jun and modulates intestinal homeostasis in mice

Authors: Vijay Pratap Singh, Saritha Katta, Satish Kumar

Published in: BMC Cancer | Issue 1/2017

Login to get access

Abstract

Background

WDR13 is a member of the WD repeat protein family and is expressed in several tissues of human and mice. Previous studies in our laboratory showed that the lack of this gene in mice resulted in mild obesity, hyperinsulinemia, enhanced beta cell proliferation and protection from inflammation. However, the molecular mechanism of WDR13 action is not well understood.

Methods

In the present study, we used AOM/DSS to induce colitis-mediated colorectal tumor after establishing expression of Wdr13 gene in colon. Further, we have used human colon cancer cell lines, HT29 and COLO205, and mouse primary embryonic fibroblast to understand the molecular mechanism of WDR13 action.

Results

We observed that mice lacking Wdr13 gene have reduced number of tumors and are more susceptible to DSS-induced colon ulcers. We also show that WDR13 is a part of multi protein complex c-Jun/NCoR1/HDAC3 and it acts as a transcriptional activator of AP1 target genes in the presence of JNK signal. Consistent with in vitro data, we observed reduced expression of AP1 target genes in colon after AOM/DSS treatment in Wdr13 knockout mice as compared to that in wild type.

Conclusion

Mice lacking Wdr13 gene showed reduced expression of AP1 target genes and protection from colitis-induced colorectal tumors.
Appendix
Available only for authorised users
Literature
1.
2.
3.
Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature. 2001;411(6835):342–8.CrossRefPubMed
4.
Mann B, Gelos M, Siedow A, Hanski ML, Gratchev A, Ilyas M, Bodmer WF, Moyer MP, Riecken EO, Buhr HJ, et al. Target genes of beta-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas. Proc Natl Acad Sci U S A. 1999;96(4):1603–8.CrossRefPubMedPubMedCentral
5.
Rao TP, Kuhl M. An updated overview on Wnt signaling pathways: a prelude for more. Circ Res. 2010;106(12):1798–806.CrossRefPubMed
6.
Radtke F, Clevers H. Self-renewal and cancer of the gut: two sides of a coin. Science. 2005;307(5717):1904–9.CrossRefPubMed
7.
Veeman MT, Axelrod JD, Moon RT. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell. 2003;5(3):367–77.CrossRefPubMed
8.
Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell. 1994;76(6):1025–37.CrossRefPubMed
9.
Saadeddin A, Babaei-Jadidi R, Spencer-Dene B, Nateri AS. The links between transcription, beta-catenin/JNK signaling, and carcinogenesis. Mol Cancer Res. 2009;7(8):1189–96.CrossRefPubMed
10.
11.
Eferl R, Wagner EF. AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer. 2003;3(11):859–68.CrossRefPubMed
12.
Mechta-Grigoriou F, Gerald D, Yaniv M. The mammalian Jun proteins: redundancy and specificity. Oncogene. 2001;20(19):2378–89.CrossRefPubMed
13.
Angel P, Hattori K, Smeal T, Karin M. The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell. 1988;55(5):875–85.CrossRefPubMed
14.
Ogawa S, Lozach J, Jepsen K, Sawka-Verhelle D, Perissi V, Sasik R, Rose DW, Johnson RS, Rosenfeld MG, Glass CK. A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation. Proc Natl Acad Sci U S A. 2004;101(40):14461–6.CrossRefPubMedPubMedCentral
15.
Pulverer BJ, Kyriakis JM, Avruch J, Nikolakaki E, Woodgett JR. Phosphorylation of c-jun mediated by MAP kinases. Nature. 1991;353(6345):670–4.CrossRefPubMed
16.
Ghisletti S, Huang W, Jepsen K, Benner C, Hardiman G, Rosenfeld MG, Glass CK. Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathways. Genes Dev. 2009;23(6):681–93.CrossRefPubMedPubMedCentral
17.
Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol. 2002;4(5):E131–6.CrossRefPubMed
18.
Sancho R, Nateri AS, de Vinuesa AG, Aguilera C, Nye E, Spencer-Dene B, Behrens A. JNK signalling modulates intestinal homeostasis and tumourigenesis in mice. EMBO J. 2009;28(13):1843–54.CrossRefPubMedPubMedCentral
19.
Singh BN, Suresh A, UmaPrasad G, Subramanian S, Sultana M, Goel S, Kumar S, Singh L. A highly conserved human gene encoding a novel member of WD-repeat family of proteins (WDR13). Genomics. 2003;81(3):315–28.CrossRefPubMed
20.
Suresh A, Shah V, Rani DS, Singh BN, Prasad GU, Subramanian S, Kumar S, Singh L. A mouse gene encoding a novel member of the WD family of proteins is highly conserved and predominantly expressed in the testis (Wdr13). Mol Reprod Dev. 2005;72(3):299–310.CrossRefPubMed
21.
Singh VP, Alex JL, Lakshmi BJ, Sailasree SP, Raj TA, Kumar S. Role of mouse Wdr13 in placental growth; a genetic evidence for lifetime body weight determination by placenta during development. Sci Rep. 2015;5:13371.CrossRefPubMedPubMedCentral
22.
Singh VP, Lakshmi BJ, Singh S, Shah V, Goel S, Sarathi DP, Kumar S. Lack of Wdr13 gene in mice leads to enhanced pancreatic beta cell proliferation, hyperinsulinemia and mild obesity. PLoS ONE. 2012;7(6):e38685.CrossRefPubMedPubMedCentral
23.
Todaro GJ, Green H. Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines. J Cell Biol. 1963;17:299–313.CrossRefPubMedPubMedCentral
24.
Neufert C, Becker C, Neurath MF. An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression. Nat Protoc. 2007;2(8):1998–2004.CrossRefPubMed
25.
Schreiber M, Kolbus A, Piu F, Szabowski A, Mohle-Steinlein U, Tian J, Karin M, Angel P, Wagner EF. Control of cell cycle progression by c-Jun is p53 dependent. Genes Dev. 1999;13(5):607–19.CrossRefPubMedPubMedCentral
26.
Stepniak E, Ricci R, Eferl R, Sumara G, Sumara I, Rath M, Hui L, Wagner EF. c-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity. Genes Dev. 2006;20(16):2306–14.CrossRefPubMedPubMedCentral
27.
Weiss C, Schneider S, Wagner EF, Zhang X, Seto E, Bohmann D. JNK phosphorylation relieves HDAC3-dependent suppression of the transcriptional activity of c-Jun. EMBO J. 2003;22(14):3686–95.CrossRefPubMedPubMedCentral
28.
Shaulian E, Schreiber M, Piu F, Beeche M, Wagner EF, Karin M. The mammalian UV response: c-Jun induction is required for exit from p53-imposed growth arrest. Cell. 2000;103(6):897–907.CrossRefPubMed
29.
Aguilera C, Nakagawa K, Sancho R, Chakraborty A, Hendrich B, Behrens A. c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex. Nature. 2011;469(7329):231–5.CrossRefPubMed
30.
Koyama-Nasu R, David G, Tanese N. The F-box protein Fbl10 is a novel transcriptional repressor of c-Jun. Nat Cell Biol. 2007;9(9):1074–80.CrossRefPubMed
31.
Zhang J, Kalkum M, Chait BT, Roeder RG. The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. Mol Cell. 2002;9(3):611–23.CrossRefPubMed
32.
Lee SK, Kim JH, Lee YC, Cheong J, Lee JW. Silencing mediator of retinoic acid and thyroid hormone receptors, as a novel transcriptional corepressor molecule of activating protein-1, nuclear factor-kappaB, and serum response factor. J Biol Chem. 2000;275(17):12470–4.CrossRefPubMed
33.
May GH, Allen KE, Clark W, Funk M, Gillespie DA. Analysis of the interaction between c-Jun and c-Jun N-terminal kinase in vivo. J Biol Chem. 1998;273(50):33429–35.CrossRefPubMed
34.
Dai T, Rubie E, Franklin CC, Kraft A, Gillespie DA, Avruch J, Kyriakis JM, Woodgett JR. Stress-activated protein kinases bind directly to the delta domain of c-Jun in resting cells: implications for repression of c-Jun function. Oncogene. 1995;10(5):849–55.PubMed
35.
Mitra S, Sameer Kumar GS, Tiwari V, Lakshmi BJ, Thakur SS, Kumar S. Implication of genetic deletion of Wdr13 in mice: mild anxiety, better performance in spatial memory task, with upregulation of multiple synaptic proteins. Front Mol Neurosci. 2016;9:73.CrossRefPubMedPubMedCentral
36.
Kardassis D, Papakosta P, Pardali K, Moustakas A. c-Jun transactivates the promoter of the human p21(WAF1/Cip1) gene by acting as a superactivator of the ubiquitous transcription factor Sp1. J Biol Chem. 1999;274(41):29572–81.CrossRefPubMed
37.
Jiao X, Katiyar S, Willmarth NE, Liu M, Ma X, Flomenberg N, Lisanti MP, Pestell RG. c-Jun induces mammary epithelial cellular invasion and breast cancer stem cell expansion. J Biol Chem. 2010;285(11):8218–26.CrossRefPubMedPubMedCentral
38.
Nateri AS, Spencer-Dene B, Behrens A. Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development. Nature. 2005;437(7056):281–5.CrossRefPubMed
39.
40.
Behrens A, Sibilia M, Wagner EF. Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat Genet. 1999;21(3):326–9.CrossRefPubMed
41.
Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, Kagnoff MF, Karin M. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004;118(3):285–96.CrossRefPubMed
42.
Saigusa S, Inoue Y, Tanaka K, Toiyama Y, Matsushita K, Kawamura M, Okugawa Y, Hiro J, Uchida K, Mohri Y, et al. Clinical significance of LGR5 and CD44 expression in locally advanced rectal cancer after preoperative chemoradiotherapy. Int J Oncol. 2012;41(5):1643–52.PubMed
43.
Lakshman M, Subramaniam V, Wong S, Jothy S. CD44 promotes resistance to apoptosis in murine colonic epithelium. J Cell Physiol. 2005;203(3):583–8.CrossRefPubMed
44.
Singh VP, Gurunathan C, Singh S, Singh B, Lakshmi BJ, Mishra AP, Kumar S. Genetic deletion of Wdr13 improves the metabolic phenotype of Lepr (db/db) mice by modulating AP1 and PPARgamma target genes. Diabetologia. 2015;58(2):384–92.CrossRefPubMed
Metadata
Title
WD-repeat protein WDR13 is a novel transcriptional regulator of c-Jun and modulates intestinal homeostasis in mice
Authors
Vijay Pratap Singh
Saritha Katta
Satish Kumar
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3118-7

Other articles of this Issue 1/2017

BMC Cancer 1/2017 Go to the issue

Research article

Tumour-associated glial host cells display a stem-like phenotype with a distinct gene expression profile and promote growth of GBM xenografts

Study protocol

Study protocol of the TIRED study: a randomised controlled trial comparing either graded exercise therapy for severe fatigue or cognitive behaviour therapy with usual care in patients with incurable cancer

Study protocol

Redefining radiotherapy for early-stage breast cancer with single dose ablative treatment: a study protocol

Correspondence

Does hair dye use really increase the risk of prostate cancer?

Research article

Societal preferences for adjuvant melanoma health states: UK and Australia

Research article

The effects of 1,4-dimethylpyridine in metastatic prostate cancer in mice
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