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TGF-β repression of Id2 induces apoptosis in gut epithelial cells

Oncogene volume 28, pages 1089–1098 (2009)Cite this article

Abstract

Transforming growth factor-β (TGF-β) regulates epithelial tissue homeostasis by activating processes that control cell cycle arrest, differentiation and apoptosis. Disruption of the TGF-β signaling pathway often occurs in colorectal cancers. Earlier, we have shown that TGF-β induces apoptosis through the transcription factor Smad3. Affymetrix oligonucleotide microarrays were used to identify TGF-β/Smad3 target genes that regulate apoptosis in rat intestinal epithelial cells (RIE-1). We found that TGF-β repressed the expression of the inhibitor of differentiation (Id) gene family. Knockdown of Id1 and Id2 gene expression induced apoptosis in RIE-1 cells, whereas overexpression of Id2 attenuated TGF-β-induced apoptosis. TranSignal Protein/DNA arrays were used to identify the hypoxia-inducing factor-1 (HIF-1) as a downstream target of TGF-β. HIF-1 is a basic helix-loop-helix protein, and overexpression of Id2 blocked HIF-1 activation by TGF-β. Furthermore, knockdown of HIF-1 blocked TGF-β-induced apoptosis. Thus, we have identified HIF-1 as a novel mediator downstream of Id2 in the pathway of TGF-β-induced apoptosis.

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References

  • Alliston T, Ko TC, Cao Y, Liang YY, Feng XH, Chang C et al. (2005). Repression of bone morphogenetic protein and activin-inducible transcription by Evi-1. J Biol Chem 280: 24227–24237.

    Article  CAS  Google Scholar 

  • Andres-Barquin PJ, Hernandez MC, Hayes TE, McKay RD, Israel MA . (1997). Id genes encoding inhibitors of transcription are expressed during in vitro astrocyte differentiation and in cell lines derived from astrocytic tumors. Cancer Res 57: 215–220.

    CAS  PubMed  Google Scholar 

  • Babyatsky MW, Podolsky DK . (1991). Growth and development in the gastrointestinal tract. In: Yamada T, Alpers DH, Owyang C and Powell DW (eds). Textbook of Gastroenterology. JB Lippincott Co: Philadelphia, pp 475–501.

    Google Scholar 

  • Cao Y, Chen L, Zhang W, Liu Y, Papaconstantinou HT, Bush CR et al. (2007). Identification of apoptotic genes mediating TGF-beta/Smad3-induced cell death in intestinal epithelial cells using a genomic approach. Am J Physiol Gastrointest Liver Physiol 292: G28–G38.

    Article  CAS  Google Scholar 

  • Cao Y, Deng C, Townsend Jr CM, Ko TC . (2006). TGF-beta inhibits Akt-induced transformation in intestinal epithelial cells. Surgery 140: 322–329.

    Article  Google Scholar 

  • Choy L, Skillington J, Derynck R . (2000). Roles of autocrine TGF-beta receptor and Smad signaling in adipocyte differentiation. J Cell Biol 149: 667–682.

    Article  CAS  Google Scholar 

  • Conery AR, Cao Y, Thompson EA, Townsend Jr CM, Ko TC, Luo K . (2004). Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol 6: 366–372.

    Article  CAS  Google Scholar 

  • Florio M, Hernandez MC, Yang H, Shu HK, Cleveland JL, Israel MA . (1998). Id2 promotes apoptosis by a novel mechanism independent of dimerization to basic helix-loop-helix factors. Mol Cell Biol 18: 5435–5444.

    Article  CAS  Google Scholar 

  • Gold LI . (1999). The role for transforming growth factor-beta (TGF-beta) in human cancer. Crit Rev Oncog 10: 303–360.

    CAS  PubMed  Google Scholar 

  • Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC . (2007). HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11: 335–347.

    Article  CAS  Google Scholar 

  • Hasskarl J, Munger K . (2002). Id proteins—tumor markers or oncogenes? Cancer Biol Ther 1: 91–96.

    Article  CAS  Google Scholar 

  • Heldin CH, Miyazono K, ten Dijke P . (1997). TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390: 465–471.

    Article  CAS  Google Scholar 

  • Kang Y, Chen CR, Massague J . (2003). A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol Cell 11: 915–926.

    Article  CAS  Google Scholar 

  • Kim D, Peng XC, Sun XH . (1999). Massive apoptosis of thymocytes in T-cell-deficient Id1 transgenic mice. Mol Cell Biol 19: 8240–8253.

    Article  CAS  Google Scholar 

  • Kim HJ, Chung H, Yoo YG, Kim H, Lee JY, Lee MO et al. (2007). Inhibitor of DNA binding 1 activates vascular endothelial growth factor through enhancing the stability and activity of hypoxia-inducible factor-1alpha. Mol Cancer Res 5: 321–329.

    Article  CAS  Google Scholar 

  • Ko TC, Bresnahan WA, Thompson EA . (1997). Intestinal cell cycle regulation. In: Meijer L, Guidet S and Philippe M (eds). Progress in Cell Cycle Research. Plenum Press: New York, pp 43–52.

    Chapter  Google Scholar 

  • Kondo M, Cubillo E, Tobiume K, Shirakihara T, Fukuda N, Suzuki H et al. (2004). A role for Id in the regulation of TGF-beta-induced epithelial-mesenchymal transdifferentiation. Cell Death Differ 11: 1092–1101.

    Article  CAS  Google Scholar 

  • Kowanetz M, Valcourt U, Bergstrom R, Heldin CH, Moustakas A . (2004). Id2 and Id3 define the potency of cell proliferation and differentiation responses to transforming growth factor beta and bone morphogenetic protein. Mol Cell Biol 24: 4241–4254.

    Article  CAS  Google Scholar 

  • Lasorella A, Noseda M, Beyna M, Yokota Y, Iavarone A . (2000). Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 407: 592–598.

    Article  CAS  Google Scholar 

  • Levy AP, Levy NS, Wegner S, Goldberg MA . (1995). Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem 270: 13333–13340.

    Article  CAS  Google Scholar 

  • Ling MT, Wang X, Tsao SW, Wong YC . (2002). Down-regulation of Id-1 expression is associated with TGF beta 1-induced growth arrest in prostate epithelial cells. Biochim Biophys Acta 1570: 145–152.

    Article  CAS  Google Scholar 

  • Lofstedt T, Jogi A, Sigvardsson M, Gradin K, Poellinger L, Pahlman S et al. (2004). Induction of ID2 expression by hypoxia-inducible factor-1: a role in dedifferentiation of hypoxic neuroblastoma cells. J Biol Chem 279: 39223–39231.

    Article  Google Scholar 

  • Massague J . (1998). TGF-beta signal transduction. Annu Rev Biochem 67: 753–791.

    Article  CAS  Google Scholar 

  • Massague J, Blain SW, Lo RS . (2000). TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 103: 295–309.

    Article  CAS  Google Scholar 

  • Nakajima T, Yageta M, Shiotsu K, Morita K, Suzuki M, Tomooka Y et al. (1998). Suppression of adenovirus E1A-induced apoptosis by mutated p53 is overcome by coexpression with Id proteins. Proc Natl Acad Sci USA 95: 10590–10595.

    Article  CAS  Google Scholar 

  • Nemetski SM, Gardner LB . (2007). Hypoxic regulation of Id-1 and activation of the unfolded protein response are aberrant in neuroblastoma. J Biol Chem 282: 240–248.

    Article  CAS  Google Scholar 

  • Nguyen KA, Cao Y, Chen JR, Townsend Jr CM, Ko TC . (2006). Dietary fiber enhances a tumor suppressor signaling pathway in the gut. Ann Surg 243: 619–625; discussion 625–7.

    Article  Google Scholar 

  • Norton JD . (2000). ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis. J Cell Sci 113 (Part 22): 3897–3905.

    CAS  PubMed  Google Scholar 

  • Norton JD, Atherton GT . (1998). Coupling of cell growth control and apoptosis functions of Id proteins. Mol Cell Biol 18: 2371–2381.

    Article  CAS  Google Scholar 

  • Parrinello S, Lin CQ, Murata K, Itahana Y, Singh J, Krtolica A et al. (2001). Id-1, ITF-2, and Id-2 comprise a network of helix-loop-helix proteins that regulate mammary epithelial cell proliferation, differentiation, and apoptosis. J Biol Chem 276: 39213–39219.

    Article  CAS  Google Scholar 

  • Sanchez-Elsner T, Botella LM, Velasco B, Corbi A, Attisano L, Bernabeu C . (2001). Synergistic cooperation between hypoxia and transforming growth factor-beta pathways on human vascular endothelial growth factor gene expression. J Biol Chem 276: 38527–38535.

    Article  CAS  Google Scholar 

  • Sanchez-Elsner T, Botella LM, Velasco B, Langa C, Bernabeu C . (2002). Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways. J Biol Chem 277: 43799–43808.

    Article  CAS  Google Scholar 

  • Sanchez-Elsner T, Ramirez JR, Sanz-Rodriguez F, Varela E, Bernabeu C, Botella LM . (2004). A cross-talk between hypoxia and TGF-beta orchestrates erythropoietin gene regulation through SP1 and Smads. J Mol Biol 336: 9–24.

    Article  CAS  Google Scholar 

  • Semenza GL . (1999). Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15: 551–578.

    Article  CAS  Google Scholar 

  • Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE . (1991). Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. Proc Natl Acad Sci USA 88: 5680–5684.

    Article  CAS  Google Scholar 

  • Shih SC, Claffey KP . (2001). Role of AP-1 and HIF-1 transcription factors in TGF-beta activation of VEGF expression. Growth Factors 19: 19–34.

    Article  CAS  Google Scholar 

  • Siegel PM, Shu W, Massague J . (2003). Mad upregulation and Id2 repression accompany transforming growth factor (TGF)-beta-mediated epithelial cell growth suppression. J Biol Chem 278: 35444–35450.

    Article  CAS  Google Scholar 

  • Sikder HA, Devlin MK, Dunlap S, Ryu B, Alani RM . (2003). Id proteins in cell growth and tumorigenesis. Cancer Cell 3: 525–530.

    Article  CAS  Google Scholar 

  • Tanaka K, Pracyk JB, Takeda K, Yu ZX, Ferrans VJ, Deshpande SS et al. (1998). Expression of Id1 results in apoptosis of cardiac myocytes through a redox-dependent mechanism. J Biol Chem 273: 25922–25928.

    Article  CAS  Google Scholar 

  • Wang GL, Semenza GL . (1995). Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 270: 1230–1237.

    Article  CAS  Google Scholar 

  • Wenger RH . (2002). Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J 16: 1151–1162.

    Article  CAS  Google Scholar 

  • Wenger RH, Stiehl DP, Camenisch G . (2005). Integration of oxygen signaling at the consensus HRE. Sci STKE 306: re12.

    Google Scholar 

  • Yokota Y, Mori S . (2002). Role of Id family proteins in growth control. J Cell Physiol 190: 21–28.

    Article  CAS  Google Scholar 

  • Zebedee Z, Hara E . (2001). Id proteins in cell cycle control and cellular senescence. Oncogene 20: 8317–8325.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D Deng, Dr D Song and Z Chen for technical support; Dr H Guo for real-time quantitative PCR assay at the Real-Time PCR Core Facility, Sealy Center for Cancer Cell Biology, UTMB; Dr C Cox Jr and F Jimenez in the Department of Pediatric Surgery, UTHSC-Houston, and M Griffin in the Flow Cytometry and Cell Sorting Core Facility, UTMB, for flow cytometric analysis. E Figueroa and S Schuenke in the Department of Surgery, UTMB, for manuscript preparation. This study was supported by a grant from the Gastrointestinal Research Interdisciplinary Program at the University of Texas Medical Branch (YC), and Public Health Service Grants R01 DK060105 (TCK), P01 DK035608 (CMT and TCK) and P50GM038529 (TCK).

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Authors and Affiliations

  1. Department of Surgery, University of Texas Health Science Center, Houston, TX, USA

    Y Cao, X Liu, W Zhang, X Deng, H Zhang & T C Ko

  2. Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL, USA

    Y Liu, L Chen & E A Thompson

  3. Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA

    C M Townsend Jr

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  1. Y Cao
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  2. X Liu
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Correspondence to Y Cao or T C Ko.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Cao, Y., Liu, X., Zhang, W. et al. TGF-β repression of Id2 induces apoptosis in gut epithelial cells. Oncogene 28, 1089–1098 (2009). https://doi.org/10.1038/onc.2008.456

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