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Activation of the TGFα autocrine loop is downstream of IGF-I receptor activation during mitogenesis in growth factor dependent human colon carcinoma cells

Oncogene volume 21, pages 2785–2796 (2002)Cite this article

Abstract

The inappropriate expression of TGFα in growth arrest contributes to malignant progression in human colon carcinoma cells. Early stage, non-progressed colon tumor cells show a down-regulation of TGFα in growth arrest and require both nutrients and growth factors for re-entry into the cell cycle. In contrast, highly progressed cells up-regulate TGFα during growth arrest and require only nutrients for re-entry. Given the importance of TGFα in malignant progression, this work addressed the regulation of TGFα expression in the early stage colon carcinoma cell line, FET. Growth-arrested FET cells down-regulated the expression of TGFα, EGFr and, in turn, EGFr activation. These quiescent cells continued to express high levels of IGF-IR protein, but IGF-IR activation was undetectable. Cell cycle re-entry required exogenous growth factor activation of the IGF-IR by insulin or IGF-I. This IGF-IR activation resulted in S phase re-entry and was accompanied by an approximate threefold induction of TGFα expression along with EGFr activation at 1 h following release from growth arrest. Activation of IGF-IR occurred within 5 min of cell-cycle re-entry. Previously identified DNA binding proteins which bind to a unique TGFα/EGF response element within the TGFα promoter were similarly induced following IGF-IR activation. The addition of EGFr neutralizing antibodies abolished the activated IGF-IR stimulated S phase re-entry. Moreover, disruption of the growth arrest associated down-regulation of TGFα in FET cells by constitutive TGFα expression abrogated the requirement for IGF-IR activation for cell cycle re-entry. Consequently, this study indicates, for the first time, that IGF-IR activation up-regulates components of the TGFα autocrine loop resulting in TGFα-mediated EGFr activation which was critical for IGF-IR mediated re-entry into the cell cycle from the growth-arrested state.

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References

  • Bates SE, Valerius EM, Ennis BWD, Bronzert A, Sheridan JP, Stampfer MR, Mendelsohn J, Lippman ME, Dickson RB . 1990 Endocrinology 126: 596–607

  • Blakesley VA, Stannard BS, Kalebic T, Helman LJ, LeRoith D . 1997 J. Endocrinol. 152: 339–344

  • Boyd D, Levine AE, Brattain DE, McKnight MK, Brattain MG . 1988 Cancer Res. 48: 2469–2474

  • Brattain MG, Brattain DE, Fine WD, Khaled FM, Marks ME, Kimball PM, Arcolano LA, Danbury BH . 1981 Oncodev. Biol. Med. 2: 355–366

  • Brattain MG, Howell G, Sun LZ, Willson JKV . 1994 Curr. Opin. Oncol. 6: 77–81

  • Brattain MG, Levine AE, Chakrabarty S, Yeoman LC, Willson JKV, Long B . 1984 Cancer Metastasis Rev. 3: 177–191

  • Campos-Gonzalez R, Glenney Jr JR . 1991a Cell. Reg. 2: 663–673

  • Campos-Gonzalez R, Glenney Jr JR . 1991b Growth Factors 4: 305–316

  • Chantret I, Barbat A, Dussaulx E, Brattain MG, Zweibaum A . 1988 Cancer Res. 48: 1936–1942

  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ . 1979 Biochemistry 18: 5294–5299

  • Coffey RJ, Graves-Deal R, Dempsey PJ, Whitehead RH, Pittelkow MR . 1992 Cell Growth Differ. 3: 347–354

  • Coppola D, Ferber A, Miura M, Sell C, D'Ambrosio C, Rubin R, Baserga R . 1994 Mol. Cell. Biol. 14: 4588–4595

  • Dignam JD, Lebowitz RM, Roeder RG . 1983 Nucl. Acids Res. 11: 707–712

  • DeLarco JE, Todaro GJ . 1978 Proc. Natl. Acad. Sci. USA 75: 4001–4005

  • Derynck R, Goeddel DVM, Ullrich A, Gutterman JU, Williams RD, Bringman TS, Berger WH . 1987 Cancer Res. 47: 707–712

  • Enoch T, Zinn K, Maniatis T . 1986 Mol. Cell. Biol. 6: 801–810

  • Gorski K, Carneireo M, Schibler U . 1986 Cell 47: 767–776

  • Gossen M, Bujard H . 1992 Proc. Natl. Acad. Sci. USA. 89: 5547–5551

  • Howell GM, Humphrey LE, Ziober BL, Awwad R, Periyasamy B, Koterba A, Li W, Willson JKV, Coleman K, Carboni J, Lynch M, Brattain MG . 1998 Mol. Cell. Biol. 18: 303–313

  • Howell GM, Ziober BL, Humphrey LE, Willson JKV, Sun L, Lynch M, Brattain MG . 1995 J. Cell Physiol. 162: 256–265

  • Huebers HA, Finch CA . 1987 Physiol. Rev. 67: 520–582

  • Jiang D, Yang H, Willson JKV, Liang J, Humphrey LE, Zborowska E, Wang D, Foster J, Fan R, Brattain MG . 1998 J. Biol. Chem. 273: 31471–31479

  • Khazaie K, Schirrmacher V, Lichtner RB . 1993 Cancer Metastasis Rev. 12: 255–274

  • Levitzki A, Gazit A . 1995 Science 267: 1782–1788

  • Liu SC, Woo A, Tsao MS . 1990 Br. J. Cancer 62: 425–429

  • McClain DA, Paterson AJ, Roos MD, Wei X, Kudlow JE . 1992 Proc. Natl. Acad. Sci. USA 89: 8150–8154

  • Mulder KM . 1991 Cancer Res. 51: 2256–2262

  • Mulder KM, Brattain MG . 1989 Mol. Endocrinol. 3: 1215–1222

  • Pietrzkowski Z, Lammers R, Carpenter G, Soderquist AM, Limardo M, Phillips PD, Ullrich A, Baserga R . 1992 Cell Growth Differ. 3: 199–205

  • Pittelkow MR, Cook PW, Shipley GD, Derynck R, Coffey Jr RJ . 1993 Cell Growth Differ. 4: 513–521

  • Roos MD, Han IO, Paterson AJ, Kudlow JE . 1996 Am. J. Physiol. 270: 803–811

  • Sandgren EP, Luetteke NC, Palmitter RD, Brinster RL, Lee DC . 1990 Cell 61: 1121–1135

  • Sayeski PP, Kudlow JE . 1996 J. Biol. Chem. 271: 15237–15243

  • Scheidereit C, Heguy A, Roeder RG . 1987 Cell 51: 783–793

  • Schlechte W, Brattain M, Boyd D . 1990 Cancer Commun. 2: 173–179

  • Schmid D . 1995 Cell Biol. Int. 19: 445–457

  • Stewart AJ, Johnson MD, May FE, Westly BR . 1990 J. Biol. Chem. 265: 21172–21178

  • Tanaka S, Imanishi K, Yoshihara M, Haruma K, Sumii K, Kajiyama G, Akamatsu S . 1991 Am. J. Pathol. 139: 123–129

  • Vassar R, Fuchs E . 1991 Genes Dev. 5: 714–727

  • Werner H, LeRoith D . 1996 Adv. Cancer Res. 68: 183–223

  • Wu SP, Theodorescu D, Kerbel R, Willson JKV, Mulder KM, Humphrey LE, Brattain MG . 1992 J. Cell Biol. 116: 187–196

  • Yang H, Jiang D, Wenhui L, Liang J, Gentry LE, Brattain MG . 2000 Oncogene 19: 1901–1914

  • Ziober BL, Willson JKV, Humphrey LE, Childress-Fields K, Brattain MG . 1993 J. Biol. Chem. 268: 691–698

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Acknowledgements

The authors thank Ms Lorraine Gilmore for preparation of the manuscript. This work was supported by NIH grants CA34432 and CA54870. Degeng Wang performed in partial fulfillment of the requirement for the PhD in biomedical sciences from the Medical College of Ohio.

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York, 14263, NY, USA

    Lisa E Humphrey, Michael G Brattain & Gillian M Howell

  2. Department of Biochemistry and Molecular Biology, Medical College of Ohio, PO Box 10008, Toledo, 43699–0008, Ohio, OH, USA

    Degeng Wang, Sandip Patil & Wenhui Li

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  1. Degeng Wang
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Correspondence to Gillian M Howell.

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Wang, D., Patil, S., Li, W. et al. Activation of the TGFα autocrine loop is downstream of IGF-I receptor activation during mitogenesis in growth factor dependent human colon carcinoma cells. Oncogene 21, 2785–2796 (2002). https://doi.org/10.1038/sj.onc.1205375

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