Abstract
Gadd45a, a growth arrest and DNA-damage gene, plays important roles in the control of cell cycle checkpoints, DNA repair and apoptosis. We show here that Gadd45a is involved in the control of cell contact inhibition and cell–cell adhesion. Gadd45a can serve as an adapter to enhance the interaction between β-catenin and Caveolin-1, and in turn induces β-catenin translocation to cell membrane for maintaining cell–cell adhesion/contact inhibition. This is coupled with reduction of β-catenin in cytoplasm and nucleus following Gadd45a induction, which is reflected by the downregulation of cyclin D1, one of the β-catenin targeted genes. Additionally, Gadd45a facilitates ultraviolet radiation-induced degradation of cytoplasmic and nuclear β-catenin in a p53-dependent manner via activation of p38 kinase. These findings define a novel link that connects Gadd45a to cell–cell adhesion and cell contact inhibition, which might contribute to the role of Gadd45a in inhibiting tumorigenesis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aberle H, Bauer A, Stappert J, Kispert A, Kemler R . (1997). beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J 16: 3797–3804.
Barker N, Clevers H . (2000). Catenins, Wnt signaling and cancer. Bioessays 22: 961–965.
Behrens J, Vakaet L, Friis R, Winterhager E, Van Roy F, Mareel MM et al. (1993). Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/beta-catenin complex in cells transformed with a temperature-sensitive v-SRC gene. J Cell Biol 120: 757–766.
Brabletz T, Jung A, Dag S, Hlubek F, Kirchner T . (1999). beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. Am J Pathol 155: 1033–1038.
Cadigan KM, Nusse R . (1997). Wnt signaling: a common theme in animal development. Genes Dev 11: 3286–3305.
Carrier F, Georgel P, Pourquier P, Blake M, Kontny H, Antinore M et al. (1999). Gadd45, a p53-responsive stress protein, modifies DNA accessibility on damaged chromatin. Mol Cell Biol 19: 1673–1685.
Carrier F, Smith ML, Bae I, Kilpatrick KE, Lansing TJ, Chen CY et al. (1994). Characterization of human Gadd45, a p53-regulated protein. J Biol Chem 269: 32672–32677.
Dietrich C, Scherwat J, Faust D, Oesch F . (2002). Subcellular localization of beta-catenin is regulated by cell density. Biochem Biophys Res Commun 292: 195–199.
Fan W, Jin S, Tong T, Zhao H, Fan F, Antinore MJ et al. (2002). BRCA1 regulates GADD45 through its interactions with the OCT-1 and CAAT motifs. J Biol Chem 277: 8061–8067.
Fornace Jr AJ, Alamo Jr I, Hollander MC . (1988). DNA damage-inducible transcripts in mammalian cells. Proc Natl Acad Sci USA 85: 8800–8804.
Galbiati F, Volonte D, Brown AM, Weinstein DE, Ben-Ze'ev A, Pestell RG et al. (2000). Caveolin-1 expression inhibits Wnt/beta-catenin/Lef-1 signaling by recruiting beta-catenin to caveolae membrane domains. J Biol Chem 275: 23368–23377.
Glenney Jr JR, Soppet D . (1992). Sequence and expression of caveolin, a protein component of caveolae plasma membrane domains phosphorylated on tyrosine in Rous sarcoma virus-transformed fibroblasts. Proc Natl Acad Sci USA 89: 10517–10521.
Gottardi CJ, Gumbiner BM . (2001). Adhesion signaling: how beta-catenin interacts with its partners. Curr Biol 11: R792–794.
Gumbiner BM . (2000). Regulation of cadherin adhesive activity. J Cell Biol 148: 399–404.
Hildesheim J, Belova GI, Tyner SD, Zhou X, Vardanian L, Fornace Jr AJ . (2004). Gadd45a regulates matrix metalloproteinases by suppressing DeltaNp63alpha and beta-catenin via p38 MAP kinase and APC complex activation. Oncogene 23: 1829–1837.
Hildesheim J, Bulavin DV, Anver MR, Alvord WG, Hollander MC, Vardanian L et al. (2002). Gadd45a protects against UV irradiation-induced skin tumors, and promotes apoptosis and stress signaling via MAPK and p53. Cancer Res 62: 7305–7315.
Hollander MC, Kovalsky O, Salvador JM, Kim KE, Patterson AD, Haines DC et al. (2001). Dimethylbenzanthracene carcinogenesis in Gadd45a-null mice is associated with decreased DNA repair and increased mutation frequency. Cancer Res 61: 2487–2491.
Hollander MC, Sheikh MS, Bulavin DV, Lundgren K, Augeri-Henmueller L, Shehee R et al. (1999). Genomic instability in Gadd45a-deficient mice. Nat Genet 23: 176–184.
Jin S, Antinore MJ, Lung FD, Dong X, Zhao H, Fan F et al. (2000). The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression. J Biol Chem 275: 16602–16608.
Jin S, Mazzacurati L, Zhu X, Tong T, Song Y, Shujuan S et al. (2003). Gadd45a contributes to p53 stabilization in response to DNA damage. Oncogene 22: 8536–8540.
Jin S, Tong T, Fan W, Fan F, Antinore MJ, Zhu X et al. (2002). GADD45-induced cell cycle G2-M arrest associates with altered subcellular distribution of cyclin B1 and is independent of p38 kinase activity. Oncogene 21: 8696–8704.
Kastan MB, Zhan Q, el-Deiry WS, Carrier F, Jacks T, Walsh WV et al. (1992). A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71: 587–597.
Kato Y, Hirano T, Yoshida K, Yashima K, Akimoto S, Tsuji K et al. (2005). Frequent loss of E-cadherin and/or catenins in intrabronchial lesions during carcinogenesis of the bronchial epithelium. Lung Cancer 48: 323–330.
Kemler R . (1993). From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet 9: 317–321.
Kitagawa M, Hatakeyama S, Shirane M, Matsumoto M, Ishida N, Hattori K et al. (1999). An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin. EMBO J 18: 2401–2410.
Kudo Y, Kitajima S, Ogawa I, Hiraoka M, Sargolzaei S, Keikhaee MR et al. (2004). Invasion and metastasis of oral cancer cells require methylation of E-cadherin and/or degradation of membranous beta-catenin. Clin Cancer Res 10: 5455–5463.
Leali D, Belleri M, Urbinati C, Coltrini D, Oreste P, Zoppetti G et al. (2001). Fibroblast growth factor-2 antagonist activity and angiostatic capacity of sulfated Escherichia coli K5 polysaccharide derivatives. J Biol Chem 276: 37900–37908.
Li G, Mitchell DL, Ho VC, Reed JC, Tron VA . (1996). Decreased DNA repair but normal apoptosis in ultraviolet-irradiated skin of p53-transgenic mice. Am J Pathol 148: 1113–1123.
Marchenko GN, Marchenko ND, Leng J, Strongin AY . (2002). Promoter characterization of the novel human matrix metalloproteinase-26 gene: regulation by the T-cell factor-4 implies specific expression of the gene in cancer cells of epithelial origin. Biochem J 363: 253–262.
Morin PJ . (1999). beta-catenin signaling and cancer. Bioessays 21: 1021–1030.
Patturajan M, Nomoto S, Sommer M, Fomenkov A, Hibi K, Zangen R et al. (2002). DeltaNp63 induces beta-catenin nuclear accumulation and signaling. Cancer Cell 1: 369–379.
Peifer M, Polakis P . (2000). Wnt signaling in oncogenesis and embryogenesis--a look outside the nucleus. Science 287: 1606–1609.
Piedra J, Miravet S, Castano J, Palmer HG, Heisterkamp N, Garcia de Herreros A et al. (2003). p120 Catenin-associated Fer and Fyn tyrosine kinases regulate beta-catenin Tyr-142 phosphorylation and beta-catenin-alpha-catenin Interaction. Mol Cell Biol 23: 2287–2297.
Ratovitski EA, Patturajan M, Hibi K, Trink B, Yamaguchi K, Sidransky D . (2001). p53 associates with and targets Delta Np63 into a protein degradation pathway. Proc Natl Acad Sci USA 98: 1817–1822.
Richard C, Liuzzo JP, Moscatelli D . (1995). Fibroblast growth factor-2 can mediate cell attachment by linking receptors and heparan sulfate proteoglycans on neighboring cells. J Biol Chem 270: 24188–24196.
Rothberg KG, Heuser JE, Donzell WC, Ying YS, Glenney JR, Anderson RG . (1992). Caveolin, a protein component of caveolae membrane coats. Cell 68: 673–682.
Salon C, Moro D, Lantuejoul S, Brichon Py P, Drabkin H, Brambilla C et al. (2004). E-cadherin-beta-catenin adhesion complex in neuroendocrine tumors of the lung: a suggested role upon local invasion and metastasis. Hum Pathol 35: 1148–1155.
Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R et al. (1999). The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA 96: 5522–5527.
Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM et al. (1994). Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science 266: 1376–1380.
Smith ML, Ford JM, Hollander MC, Bortnick RA, Amundson SA, Seo YR et al. (2000). p53-mediated DNA repair responses to UV radiation: studies of mouse cells lacking p53, p21, and/or gadd45 genes. Mol Cell Biol 20: 3705–3714.
Tong T, Ji J, Jin S, Li X, Fan W, Song Y et al. (2005). Gadd45a expression induces Bim dissociation from the cytoskeleton and translocation to mitochondria. Mol Cell Biol 25: 4488–4500.
van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A et al. (2002). The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111: 241–250.
Vizirianakis IS, Chen YQ, Kantak SS, Tsiftsoglou AS, Kramer RH . (2002). Dominant-negative E-cadherin alters adhesion and reverses contact inhibition of growth in breast carcinoma cells. Int J Oncol 21: 135–144.
Wang W, Huper G, Guo Y, Murphy SK, Olson Jr JA, Marks JR . (2005). Analysis of methylation-sensitive transcriptome identifies GADD45a as a frequently methylated gene in breast cancer. Oncogene 24: 2705–2714.
Wang XW, Zhan Q, Coursen JD, Khan MA, Kontny HU, Yu L et al. (1999). GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci USA 96: 3706–3711.
Yamasawa K, Nio Y, Dong M, Yamaguchi K, Itakura M . (2002). Clinicopathological significance of abnormalities in Gadd45 expression and its relationship to p53 in human pancreatic cancer. Clin Cancer Res 8: 2563–2569.
Zhan Q . (2005). Gadd45a, a p53- and BRCA1-regulated stress protein, in cellular response to DNA damage. Mutat Res 569: 133–143.
Zhan Q, Antinore MJ, Wang XW, Carrier F, Smith ML, Harris CC et al. (1999). Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 18: 2892–2900.
Zhang X, Ma L, Enkemann SA, Pledger WJ . (2003). Role of Gadd45alpha in the density-dependent G1 arrest induced by p27(Kip1). Oncogene 22: 4166–4174.
Acknowledgements
We thank Professor Albert J Fornace of University of Harvard and M Christine Hollander of NIH for the immortalized Gadd45a−/− and matching +/+ MEF cells and Professor Bert Vogelstein of Johns Hopkins for HCT 116 p53 −/− and matching +/+ cells. This work was supported in part by the National Fundamental Research Program of China (2002CB513101) and the National Natural Science Foundation of China (30225018 and 30400074).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ji, J., Liu, R., Tong, T. et al. Gadd45a regulates β-catenin distribution and maintains cell–cell adhesion/contact. Oncogene 26, 6396–6405 (2007). https://doi.org/10.1038/sj.onc.1210469
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1210469
Keywords
This article is cited by
-
GADD45G Interacts with E-cadherin to Suppress the Migration and Invasion of Esophageal Squamous Cell Carcinoma
Digestive Diseases and Sciences (2020)
-
Notch3-dependent β-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC
Nature Communications (2018)
-
Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway
Oncogene (2009)