Abstract
Insulin-like growth factors (IGF-I and IGF-II) play a crucial role in regulating cell proliferation and differentiation. The IGFs have mitogenic and antiapoptotic effects on normal and transformed cells. These peptide growth factors are produced by virtually all tissues and act in an endocrine, autocrine, and paracrine fashion. The endocrine form of IGF-I originates mostly (75%) from the liver and IGF-binding proteins regulate its bioactivity. Compared to other peptide growth factors, the IGFs are in abundant supply in circulation. The role of this large reservoir of IGFs has been debated for many years. In the last few years substantial progress has been made in understanding the function of the endocrine IGF-I using new animal models. This review will revisit the IGF system with particular attention to the role of circulating IGF-I in growth regulation, metabolism, and cancer.
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Salomon, W. D. and Daughaday, D. W. (1957). J. Lab. Clin. Med. 49, 825–826.
Isaksson, O. G., Jansson, J. O., and Gause, I. A. (1982). Science 216, 1237–1239.
D’Ercole, A. J., Applewhite, G. T., and Underwood, L. E. (1980). Dev. Biol. 75, 315–328.
D’Ercole, A. J., Stiles, A. D., and Underwood, L. E. (1984). Proc. Natl. Acad. Sci. USA 81, 935–939.
Isgaard, J., Nilsson, A., Lindahl, A., Jansson, J. O., and Isaksson, O. G. (1986). Am. J. Physiol. 250, E367-E372.
Lowe, W. L. Jr., Lasky, S. R., LeRoith, D., and Roberts, C. T. Jr. (1988). Mol. Endocrinol. 2, 528–535.
Roberts, C. T. Jr., Lasky, S. R., Lowe, W. L. Jr., Seaman, W. T., and LeRoith, D. (1987). Mol. Endocrinol. 1, 243–248.
Rotwein, P., Pollock, K. M., Didier, D. K., and Krivi, G. G. (1986). J. Biol. Chem. 261, 4828–4832.
Shimatsu, A. and Rotwein, P. (1987). Nucleic Acids Res. 15, 7196.
Wong, E. A., Ohlsen, S. M., Godfredson, J. A., Dean, D. M., and Wheaton, J. E. (1989). DNA 8, 649–657.
Adamo, M. L., Ben-Hur, H., Roberts, C. T. Jr., and LeRoith, D. (1991). Mol. Endocrinol. 5, 1677–1686.
Hoyt, E. C., Van Wyk, J. J., and Lund, P. K. (1988). Mol. Endocrinol. 2, 1077–1086.
Kikuchi, K., Bichell, D. P., and Rotwein, P. (1992). J. Biol. Chem. 267, 21505–21511.
Hall, L. J., Kajimoto, Y., Bichell, D., et al. (1992). DNA Cell Biol. 11, 301–313.
Jones, J. I. and Clemmons, D. R. (1995). Endocr. Rev. 16, 3–34.
Clemmons, D. R., Busby, W., Clarke, J. B., Parker, A., Duan, C., and Nam, T. J. (1998). Endocr. J. 45(Suppl.), S1-S8.
Binoux, M. and Hossenlopp, P. (1988). J. Clin. Endocrinol. Metab. 67, 509–514.
Bar, R. S., Clemmons, D. R., Boes, M., et al. (1990). Endocrinology 127, 1078–1086.
Le Roith, D., Bondy, C., Yakar, S., Liu, J. L., and Butler, A. (2001). Endocr. Rev. 22, 53–74.
Imai, Y., Busby, W. H. Jr., Smith, C. E., et al. (1997). J. Clin. Invest. 100, 2596–2605.
Bagi, C. M., Brommage, R., Deleon, L., Adams, S., Rosen, D., and Sommer, A. (1994). J. Bone Miner. Res. 9, 1301–1312.
Schneider, M. R., Lahm, H., Wu, M., Hoeflich, A., and Wolf, E. (2000). FASEB J. 14, 629–640.
Bichell, D. P., Kikuchi, K., and Rotwein, P. (1992). Mol. Endocrinol. 6, 1899–1908.
Mathews, L. S., Norstedt, G., and Palmiter, R. D. (1986). Proc. Natl. Acad. Sci. USA 83, 9343–9347.
Pell, J. M., Saunders, J. C., and Gilmour, R. S. (1993). Endocrinology 132, 1797–1807.
Bornfeldt, K. E., Arnqvist, H. J., Enberg, B., Mathews, L. S., and Norstedt, G. (1989). J. Endocrinol. 122, 651–656.
Boni-Schnetzler, M., Schmid, C., Meier, P. J., and Froesch, E. R. (1991). Am. J. Physiol. 260, E846-E851.
Kachra, Z., Barash, I., Yannopoulos, C., Khan, M. N., Guyda, H. J., and Posner, B. I. (1991). Endocrinology 128, 1723–1730.
Delany, A. M. and Canalis, E. (1995). Endocrinology 136, 4776–4781.
Murphy, L. J. and Friesen, H. G. (1988). Endocrinology 122, 325–332.
Delafontaine, P. (1995). Cardiovasc. Res. 30, 825–834.
Dorshkind, K. and Horseman, N. D. (2000). Endocr. Rev. 21, 292–312.
Chernausek, S. D., Underwood, L. E., and Van Wyk, J. J. (1982). Endocrinology 111, 1534–1538.
Miell, J. P., Taylor, A. M., Zini, M., Maheshwari, H. G., Ross, R. J., and Valcavi, R. (1993). J. Clin. Endocrinol. Metab. 76, 950–955.
Mayo, K. E. (1992). Mol. Endocrinol. 6, 1734–1744.
Korytko, A. I. and Cuttler, L. (1997). J. Endocrinol. 152, R13-R17.
Grant, M. B., Mames, R. N., Fitzgerald, C., Ellis, E. A., Aboufriekha, M., and Guy, J. (1993). Diabetologia 36, 282–291.
Kovacs, E. J. and DiPietro, L. A. (1994). FASEB J. 8, 854–861.
Suh, D. Y., Hunt, T. K., and Spencer, E. M. (1992). Endocrinology 131, 2399–2403.
Yateman, M. E., Claffey, D. C., Cwyfan Hughes, S. C., Frost, V. J., Wass, J. A., and Holly, J. M. (1993). J. Endocrinol. 137, 151–159.
Savendahl, L., Underwood, L. E., Haldeman, K. M., Ulshen, M. H., and Lund, P. K. (1997). Endocrinology 138, 734–740.
Zimmermann, E. M., Sartor, R. B., McCall, R. D., Pardo, M., Bender, D., and Lund, P. K. (1993). Gastroenterology 105, 399–409.
Arkins, S., Rebeiz, N., Biragyn, A., Reese, D. L., and Kelley, K. W. (1993). Endocrinology 133, 2334–2343.
Arkins, S., Rebeiz, N., Brunke-Reese, D. L., Minshall, C., and Kelley, K. W. (1995). Endocrinology 136, 1153–1160.
Kirstein, M., Aston, C., Hintz, R., and Vlassara, H. (1992). J. Clin. Invest. 90, 439–446.
Lake, F. R., Noble, P. W., Henson, P. M., and Riches, D. W. (1994). J. Clin. Invest. 93, 1661–1669.
Arkins, S., Rebeiz, N., Brunke-Reese, D. L., Biragyn, A., and Kelley, K. W. (1995). Mol. Endocrinol. 9, 350–360.
Min, S. H., MacKenzie, D. D., Breier, B. H., McCutcheon, S. N., and Gluckman, P. D. (1996). Endocrinology 137, 1129–1137.
Thissen, J. P., Triest, S., Underwood, L. E., Maes, M., and Ketelslegers, J. M. (1990). Endocrinology 126, 908–913.
Tomas, F. M., Knowles, S. E., Chandler, C. S., Francis, G. L., Owens, P. C., and Ballard, F. J. (1993). J. Endocrinol. 137, 413–421.
Sanchez-Gomez, M., Malmlof, K., Mejia, W., et al. (1999). Br. J. Nutr. 81, 145–157.
Thissen, J. P., Ketelslegers, J. M., and Underwood, L. E. (1994). Endocr. Rev. 15, 80–101.
Underwood, L. E. (1996). J. Pediatr. Endocrinol. Metab. 9(Suppl. 3), 303–312.
Brogan, R. S., Fife, S. K., Conley, L. K., Giustina, A., and Wehrenberg, W. B. (1997). Neuroendocrinology 65, 129–135.
Baker, J., Liu, J. P., Robertson, E. J., and Efstratiadis, A. (1993). Cell 75, 73–82.
Powell-Braxton, L., Hollingshead, P., Warburton, C., et al. (1993). Genes Dev. 7, 2609–2617.
Liu, J. L., Grinberg, A., Westphal, H., et al. (1998). Mol. Endocrinol. 12, 1452–1462.
Liu, J. P., Baker, J., Perkins, A. S., Robertson, E. J., and Efstratiadis, A. (1993). Cell 75, 59–72.
Zhou, Y., Xu, B. C., Maheshwari, H. G., et al. (1997). Proc. Natl. Acad. Sci. USA 94, 13215–13220.
Donahue, L. R. and Beamer, W. G. (1993). J. Endocrinol. 136, 91–104.
Yakar, S., Liu, J. L., Stannard, B., et al. (1999). Proc. Natl. Acad. Sci. USA 96, 7324–7329.
Yakar, S., Rosen, C. J., Beamer, W. G., et al. (2002). J. Clin. Invest. 110, 771–781.
Ueki, I., Ooi, G. T., Tremblay, M. L., Hurst, K. R., Bach, L. A., and Boisclair, Y. R. (2000). Proc. Natl. Acad. Sci. USA 97, 6868–6873.
Silha, J. V., Gui, Y., Modric, T., et al. (2001). Endocrinology 142, 4305–4313.
Gay, E., Seurin, D., Babajko, S., Doublier, S., Cazillis, M., and Binoux, M. (1997). Endocrinology 138, 2937–2947.
D’Ercole, A. J., Dai, Z., Xing, Y., et al. (1994). Brain Res. Dev. Brain Res. 82, 213–222.
Dai, Z., Xing, Y., Boney, C. M., Clemmons, D. R., and D’Ercole, A. J. (1994). Endocrinology 135, 1316–1327.
Huang, H., Rajkumar, K., and Murphy, L. J. (1997). J. Endocrinol. 152, 99–108.
Rajkumar, K., Barron, D., Lewitt, M. S., and Murphy, L. J. (1995). Endocrinology 136, 4029–4034.
Hoeflich, A., Wu, M., Mohan, S., et al. (1999). Endocrinology 140, 5488–5496.
Murphy, L. J., Molnar, P., Lu, X., and Huang, H. (1995). J. Mol. Endocrinol. 15, 293–303.
Neuenschwander, S., Schwartz, A., Wood, T. L., Roberts, C. T. Jr., Henninghausen, L., and LeRoith, D. (1996). J. Clin. Invest. 97, 2225–2232.
Wang, J., Niu, W., Witte, D. P., et al. (1998). Endocrinology 139, 2605–2614.
Wood, T. L., Rogler, L. E., Czick, M. E., Schuller, A. G., and Pintar, J. E. (2000). Mol. Endocrinol. 14, 1472–1482.
Rosen, C. J. and Donahue, L. R. (1998). Proc. Soc. Exp. Biol. Med. 219, 1–7.
Rosen, C. J., Donahue, L. R., and Hunter, S. J. (1994). Proc. Soc. Exp. Biol. Med. 206, 83–102.
Hayden, J. M., Mohan, S., and Baylink, D. J. (1995). Bone 17, 93S-98S.
Langlois, J. A., Rosen, C. J., Visser, M., et al. (1998). J. Clin. Endocrinol. Metab. 83, 4257–4262.
Gamero, P., Sornay-Rendu, E., and Delmas, P. D. (2000). Lancet 355, 898–899.
Wolf, E., Rapp, K., Blum, W. F., Kolb, H., and Brem, G. (1995). Growth Regul. 5, 177–183.
D’Ercole, A. J. (1993). Ann. NY Acad. Sci. 692, 149–160.
Bikle, D., Majumdar, S., Laib, A., et al. (2001). J. Bone Miner. Res. 16, 2320–2329.
Zhang, M., Xuan, S., Bouxein, M. L., et al. (2002). J. Biol. Chem. 277, 44005–44012.
Beamer, W. H. and Eicher, E. M. (1976). J. Endocrinol. 71, 37–45.
Beamer, W. G., Shultz, K. L., Donahue, L. R., et al. (2001). J. Bone Miner. Res. 16, 1195–1206.
Richman, C., Kutilek, S., Miyakoshi, N., et al. (2001). J. Bone Miner. Res. 16, 386–397.
Sims, N. A., Clement-Lacroix, P., Da Ponte, F., et al. (2000). J. Clin. Invest. 106, 1095–1103.
Lupu, F., Terwilliger, J. D., Lee, K., Segre, G. V., and Efstratiadis, A. (2001). Dev. Biol. 229, 141–162.
Lamothe, B., Baudry, A., Desbois, P., et al. (1998). Biochem. J. 335(Pt. 2), 193–204.
Accili, D., Drago, J., Lee, E. J., et al. (1996). Nat. Genet. 12, 106–109.
Bruning, J. C., Michael, M. D., Winnay, J. N., et al. (1998). Mol. Cell. 2, 559–569.
Kulkarni, R. N., Bruning, J. C., Winnay, J. N., Postic, C., Magnuson, M. A., and Kahn, C. R. (1999). Cell 96, 329–339.
Tamemoto, H., Kadowaki, T., Tobe, K., et al. (1994). Nature 372, 182–186.
Kido, Y., Burks, D. J., Withers, D., et al. (2000). J. Clin. Invest. 105, 199–205.
Froesch, E. R., Hussain, M. A., Schmid, C., and Zapf, J. (1996). Diabetes Metab. Rev. 12, 195–215.
Yakar, S., Liu, J. L., Fernandez, A. M., et al. (2001). Diabetes 50, 1110–1118.
Dominici, F. P. and Turyn, D. (2002). Exp. Biol. Med. (Maywood) 227, 149–157.
Balbis, A., Dellacha, J. M., Calandra, R. S., Bartke, A., and Turyn, D. (1992). Life Sci. 51, 771–778.
Balbis, A., Bartke, A., and Turyn, D. (1996). Life Sci 59, 1363–1371.
Kovacs, M., Schally, A. V., Zarandi, M., and Groot, K. (1997). Peptides 18, 431–438.
Kopchick, J. J., Bellush, L. L., and Coschigano, K. T. (1999). Annu. Rev. Nutr. 19, 437–461.
Moller, D. E. and Flier, J. S. (1991). N. Engl. J. Med. 325, 938–948.
Shalev, A. (1999). Eur. J. Endocrinol. 141, 323–324.
Dominici, F. P., Arostegui Diaz, G., Bartke, A., Kopchick, J. J., and Turyn, D. (2000). J. Endocrinol. 166, 579–590.
Smith, T. R., Elmendorf, J. S., David, T. S., and Turinsky, J. (1997). Am. J. Physiol. 272, E1071-E1079.
Thirone, A. C., Carvalho, C. R., Brenelli, S. L., Velloso, L. A., and Saad, M. J. (1997). Mol. Cell. Endocrinol. 130, 33–42.
Qiao, L. Y., Goldberg, J. L., Russell, J. C., and Sun, X. J. (1999). J. Biol. Chem. 274, 10625–10632.
LeRoith, D., Baserga, R., Helman, L., and Roberts, C. T., Jr. (1995). Ann. Intern. Med. 122, 54–59.
Baserga, R. (1995). Cancer Res. 55, 249–252.
Ma, J., Pollak, M. N., Giovannucci, E., et al. (1999). J. Natl. Cancer Inst. 91, 620–625.
Hankinson, S. E., Willett, W. C., Colditz, G. A., et al. (1998). Lancet 351, 1393–1396.
Chan, J. M., Stampfer, M. J., Giovannucci, E., et al. (1998). Science 279, 563–566.
Wolk, A., Mantzoros, C. S., Andersson, S. O., et al. (1998). J. Natl. Cancer Inst. 90, 911–915.
Yu, H., Spitz, M. R., Mistry, J., Gu, J., Hong, W. K., and Wu, X. (1999). J. Natl. Cancer Inst. 91, 151–156.
Renehan, A. G., Painter, J. E., Atkin, W. S., Potten, C. S., Shalet, S. M., and O’Dwyer, S. T. (2001). Br. J. Surg. 88, 107–113.
Jenkins, P. J., Fairclough, P. D., Richards, T., et al. (1997). Clin. Endocrinol. (Oxf.) 47, 17–22.
Wu, Y., Yakar, S., Zhao, L., Hennighausen, L., and LeRoith, D. (2002). Cancer Res. 62, 1030–1035.
Dunger, D. B. and Acerini, C. L. (1997). Diabet. Med. 14, 723–731.
Hammerman, M. R. and Miller, S. B. (1997). J. Pediatr. 131, S17-S19.
Jenkins, R. C. and Ross, R. J. (1996). QJM 89, 813–819.
Borst, S. E. and Lowenthal, D. T. (1997). Endocrine 7, 61–63.
Barni, S., Lissoni, P., Brivio, F., et al. (1994). Tumori 80, 212–215.
Peyrat, J. P., Bonneterre, J., Hecquet, B., et al. (1993). Eur. J. Cancer 29A, 492–497.
Bhatavdekar, J. M., Patel, D. D., Karelia, N. H., et al. (1994). Breast Cancer Res. Treat. 30, 293–297.
Albanes, D. (1987). Cancer Res. 47, 1987–1992.
Ruggeri, B. A., Klurfeld, D. M., Kritchevsky, D., and Furlanetto, R. W. (1989). Cancer Res. 49, 4135–4141.
Yang, X. F., Beamer, W. G., Huynh, H., and Pollak, M. (1996). Cancer Res. 56, 1509–1511.
Tornell, J., Carlsson, B., Pohjanen, P., Wennbo, H., Rymo, L., and Isaksson, O. (1992). J. Steroid Biochem. Mol. Biol. 43, 237–242.
Tornell, J., Rymo, L., and Isaksson, O. G. (1991). Int. J. Cancer 49, 114–117.
Chen, N. Y., Chen, W. Y., Striker, L. J., Striker, G. E., and Kopchick, J. J. (1997). Endocrinology 138, 851–854.
McGuire, W. L. Jr., Jackson, J. G., Figueroa, J. A., Shimasaki, S., Powell, D. R., and Yee, D. (1992). J. Natl. Cancer Inst. 84, 1336–1341.
Yee, D., Sharma, J., and Hilsenbeck, S. G. (1994). J. Natl. Cancer Inst. 86, 1785–1789.
Shao, Z. M., Sheikh, M. S., Ordonez, J. V., et al. (1992). Cancer Res. 52, 5100–5103.
Clemmons, D. R., Camacho-Hubner, C., Coronado, E., and Osborne, C. K. (1990). Endocrinology 127, 2679–2686.
Capony, F., Rougeot, C., Montcourrier, P., Cavailles, V., Salazar, G., and Rochefort, H. (1989). Cancer Res. 49, 3904–3909.
Conover, C. A. and De Leon, D. D. (1994). J. Biol. Chem. 269, 7076–7080.
Yu, H., Diamandis, E. P., and Sutherland, D. J. (1994). Clin. Biochem. 27, 75–79.
Schmitt, M., Goretzki, L., Janicke, F., et al. (1991). Biomed. Biochim. Acta 50, 731–741.
Lee, D. Y., Park, S. K., Yorgin, P. D., Cohen, P., Oh, Y., and Rosenfeld, R. G. (1994). J. Clin. Endocrinol. Metab. 79, 1376–1382.
Oh, Y. (1998). Breast Cancer Res. Treat. 47, 283–293.
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Yakar, S., Wu, Y., Setser, J. et al. The role of circulating IGF-I. Endocr 19, 239–248 (2002). https://doi.org/10.1385/ENDO:19:3:239
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DOI: https://doi.org/10.1385/ENDO:19:3:239