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Gene Review

TDGF1  -  teratocarcinoma-derived growth factor 1

Homo sapiens

Synonyms: CR, CRGF, CRIPTO, Cripto-1, Cripto-1 growth factor, ...
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Disease relevance of TDGF1

  • Eighty-two percent of breast carcinomas express Cr-1 whereas it is undetected in normal human breast tissue [1].
  • All 18 patients in CR1 had one or more poor risk factors: age more than 18 (N = 17), initial leukocyte count greater than or equal to 20,000 (N = 11), Ph 1 chromosome (N = 2), delay in attaining CR more than 6 weeks (N = 8), or extramedullary disease (N = 1) [2].
  • Cripto-1 overexpression leads to enhanced invasiveness and resistance to anoikis in human MCF-7 breast cancer cells [3].
  • In addition, AR and CRIPTO immunoreactivity were found in 11 and in 26 out of 55 DCIS respectively [4].
  • AR and CRIPTO immunoreactivity was also assessed in 55 human breast ductal carcinomas in situ (DCIS) [4].

High impact information on TDGF1

  • To test whether CR ligands could be generated by the B cell receptor (BCR) itself, we generated similar mice carrying a mutated mIgM that was defective in C1q binding [5].
  • Immunized CR knockout (KO) mice have lower antibody titers and smaller germinal centers (GCs), demonstrating the importance of CR signals for the humoral immune response [5].
  • Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo [6].
  • Thus, the enhanced phagocytosis and killing of opsonized bacteria by collagen-adherent monocytes appear to be by regulation of the function of membrane CR and FcR, without apparent enhancement of the respiratory burst [7].
  • Adherence of monocytes to collagen gels activated C receptors (CR) types 1 and 3 for phagocytosis, and enhanced Fc receptor (FcR)-mediated phagocytosis [7].

Chemical compound and disease context of TDGF1


Biological context of TDGF1

  • We propose a model in which Cripto has dual roles as a coreceptor as well as a coligand for Nodal and that this signaling interaction with Nodal is regulated by an unusual form of glycosylation [13].
  • Infection of CID 9 cells with a Cr-1 antisense vector caused these cells to change in morphology, to grow slowly, to undergo apoptosis at a higher rate and to achieve lower saturation densities but the cells were still capable of differentiating [1].
  • We concluded that Cr-1 is an autocrine growth factor for normal breast cells, that when over-expressed stimulates excessive cell proliferation at the expense of differentiation [1].
  • Exogenous mouse Cr-1 expression from a retroviral vector caused CID 9 cells to grow at an increased rate and to increased cell densities compared to parental and control cells [1].
  • Assignment of human teratocarcinoma derived growth factor (TDGF) sequences to chromosomes 2q37, 3q22, 6p25 and 19q13.1 [14].

Anatomical context of TDGF1


Associations of TDGF1 with chemical compounds

  • We have found that the EGF-CFC family member human Cripto-1 (CR) is modified with fucose and through a combination of peptide mapping, mass spectrometry, and sequence analysis localized the site of attachment to Thr-88 [18].
  • Finally, the apoptotic effect of LY294002 can be partially rescued by exogenous CR-1 [19].
  • Histamine has been well tolerated, and 21/22 CR patients have treated themselves at home throughout the trial [20].
  • However, the combination of taxol (5 x 10(-4) M) and NOC (2 x 10(-6) M) augmented M phi CR-mediated phagocytosis [21].
  • In these studies Candida were found to mimic the human CR by binding erythrocytes coated with specific human C3 fragments [22].

Physical interactions of TDGF1

  • Cripto has important roles during development and oncogenesis and binds nodal or related ligands and ALK4 to facilitate assembly of type I and type II receptor signaling complexes [23].
  • Here we show that Cripto can form a complex with activin and ActRII/IIB [23].

Regulatory relationships of TDGF1

  • In addition, Cripto blocked activin signaling when transfected into either HepG2 cells or 293T cells [23].
  • Cripto-1 induces phosphatidylinositol 3'-kinase-dependent phosphorylation of AKT and glycogen synthase kinase 3beta in human cervical carcinoma cells [19].
  • IL-10 almost completely reversed the IFN-gamma-induced inhibition of both Fc gamma R- and CR-mediated phagocytosis, without concomitant changes in membrane expression of phagocytic receptors [24].
  • Consistent with its ability to block receptor assembly, Cripto suppressed TGF-beta signaling in multiple cell types and diminished the cytostatic effects of TGF-beta in mammary epithelial cells [25].
  • Purified BPI completely inhibited CR up-regulation on neutrophils stimulated with both rough and smooth LPS chemotypes at 1.8 to 3.6 nM (100 to 200 ng/ml) [26].
  • Transmembrane forms of CR-1 partially retained their ability to induce Nodal signaling only when type I receptor Activin-like kinase 4 was overexpressed [27].
  • Shedding of CR-1 occurs at the GPI-anchorage site by the activity of GPI-phospholipase D (GPI-PLD), because CR-1 shedding was suppressed by siRNA knockdown of GPI-PLD and enhanced by overexpression of GPI-PLD [28].

Other interactions of TDGF1

  • Using a luciferase reporter assay, we found that Cripto has activities consistent with its being a coreceptor for Nodal [13].
  • A number of genes were down-regulated, which included LAR, ABL2, SKY, TDGF1 etc [29].
  • In summary, our data suggest that human CR-1 may function as a survival factor through a PI3K-dependent signaling pathway involving AKT and GSK-3beta [19].
  • We have also shown that under conditions in which Cripto facilitates nodal signaling, it antagonizes activin [23].
  • They also expressed high levels of amphiregulin but did not express EGF and cripto [30].

Analytical, diagnostic and therapeutic context of TDGF1


  1. Cripto: roles in mammary cell growth, survival, differentiation and transformation. Niemeyer, C.C., Persico, M.G., Adamson, E.D. Cell Death Differ. (1998) [Pubmed]
  2. Allogeneic bone marrow transplantation for patients with high-risk acute lymphoblastic leukemia. Wingard, J.R., Piantadosi, S., Santos, G.W., Saral, R., Vriesendorp, H.M., Yeager, A.M., Burns, W.H., Ambinder, R.F., Braine, H.G., Elfenbein, G. J. Clin. Oncol. (1990) [Pubmed]
  3. Cripto-1 overexpression leads to enhanced invasiveness and resistance to anoikis in human MCF-7 breast cancer cells. Normanno, N., De Luca, A., Bianco, C., Maiello, M.R., Carriero, M.V., Rehman, A., Wechselberger, C., Arra, C., Strizzi, L., Sanicola, M., Salomon, D.S. J. Cell. Physiol. (2004) [Pubmed]
  4. Differential immunohistochemical detection of transforming growth factor alpha, amphiregulin and CRIPTO in human normal and malignant breast tissues. Panico, L., D'Antonio, A., Salvatore, G., Mezza, E., Tortora, G., De Laurentiis, M., De Placido, S., Giordano, T., Merino, M., Salomon, D.S., Mullick, W.J., Pettinato, G., Schnitt, S.J., Bianco, A.R., Ciardiello, F. Int. J. Cancer (1996) [Pubmed]
  5. The B cell receptor itself can activate complement to provide the complement receptor 1/2 ligand required to enhance B cell immune responses in vivo. Rossbacher, J., Shlomchik, M.J. J. Exp. Med. (2003) [Pubmed]
  6. Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo. Adkins, H.B., Bianco, C., Schiffer, S.G., Rayhorn, P., Zafari, M., Cheung, A.E., Orozco, O., Olson, D., De Luca, A., Chen, L.L., Miatkowski, K., Benjamin, C., Normanno, N., Williams, K.P., Jarpe, M., LePage, D., Salomon, D., Sanicola, M. J. Clin. Invest. (2003) [Pubmed]
  7. Regulation of human monocyte/macrophage function by extracellular matrix. Adherence of monocytes to collagen matrices enhances phagocytosis of opsonized bacteria by activation of complement receptors and enhancement of Fc receptor function. Newman, S.L., Tucci, M.A. J. Clin. Invest. (1990) [Pubmed]
  8. Synergistic growth inhibition and induction of apoptosis by a novel mixed backbone antisense oligonucleotide targeting CRIPTO in combination with C225 anti-EGFR monoclonal antibody and 8-Cl-cAMP in human GEO colon cancer cells. Normanno, N., Tortora, G., De Luca, A., Pomatico, G., Casamassimi, A., Agrawal, S., Mendelsohn, J., Bianco, A.R., Ciardiello, F. Oncol. Rep. (1999) [Pubmed]
  9. Hematopoietic stem cell transplantation for childhood myeloid malignancies after high-dose thiotepa, busulfan and cyclophosphamide. Worth, L., Tran, H., Petropoulos, D., Culbert, S., Mullen, C., Roberts, W., Przepiorka, D., Chan, K. Bone Marrow Transplant. (1999) [Pubmed]
  10. Regulation of 3alpha-hydroxysteroid dehydrogenase/carbonyl reductase in Comamonas testosteroni: function and relationship of two operators. Xiong, G., Markowetz, S., Maser, E. Chem. Biol. Interact. (2003) [Pubmed]
  11. 3alpha-Hydroxysteroid dehydrogenase/carbonyl reductase from Comamonas testosteroni: biological significance, three-dimensional structure and gene regulation. Maser, E., Xiong, G., Grimm, C., Ficner, R., Reuter, K. Chem. Biol. Interact. (2001) [Pubmed]
  12. Graft-versus-host disease is associated with a lower relapse incidence after hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia. Nordlander, A., Mattsson, J., Ringdén, O., Leblanc, K., Gustafsson, B., Ljungman, P., Svenberg, P., Svennilson, J., Remberger, M. Biol. Blood Marrow Transplant. (2004) [Pubmed]
  13. Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway. Yan, Y.T., Liu, J.J., Luo, Y., E, C., Haltiwanger, R.S., Abate-Shen, C., Shen, M.M. Mol. Cell. Biol. (2002) [Pubmed]
  14. Assignment of human teratocarcinoma derived growth factor (TDGF) sequences to chromosomes 2q37, 3q22, 6p25 and 19q13.1. Scognamiglio, B., Baldassarre, G., Cassano, C., Tucci, M., Montuori, N., Dono, R., Lembo, G., Barra, A., Lago, C.T., Viglietto, G., Rocchi, M., Persico, M.G. Cytogenet. Cell Genet. (1999) [Pubmed]
  15. Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells. Bianco, C., Adkins, H.B., Wechselberger, C., Seno, M., Normanno, N., De Luca, A., Sun, Y., Khan, N., Kenney, N., Ebert, A., Williams, K.P., Sanicola, M., Salomon, D.S. Mol. Cell. Biol. (2002) [Pubmed]
  16. A truncated form of teratocarcinoma-derived growth factor-1 (cripto-1) mRNA expressed in human colon carcinoma cell lines and tumors. Baldassarre, G., Tucci, M., Lembo, G., Pacifico, F.M., Dono, R., Lago, C.T., Barra, A., Bianco, C., Viglietto, G., Salomon, D., Persico, M.G. Tumour Biol. (2001) [Pubmed]
  17. Differential expression of epidermal growth factor-related proteins in human colorectal tumors. Ciardiello, F., Kim, N., Saeki, T., Dono, R., Persico, M.G., Plowman, G.D., Garrigues, J., Radke, S., Todaro, G.J., Salomon, D.S. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  18. Fucosylation of Cripto is required for its ability to facilitate nodal signaling. Schiffer, S.G., Foley, S., Kaffashan, A., Hronowski, X., Zichittella, A.E., Yeo, C.Y., Miatkowski, K., Adkins, H.B., Damon, B., Whitman, M., Salomon, D., Sanicola, M., Williams, K.P. J. Biol. Chem. (2001) [Pubmed]
  19. Cripto-1 induces phosphatidylinositol 3'-kinase-dependent phosphorylation of AKT and glycogen synthase kinase 3beta in human cervical carcinoma cells. Ebert, A.D., Wechselberger, C., Frank, S., Wallace-Jones, B., Seno, M., Martinez-Lacaci, I., Bianco, C., De Santis, M., Weitzel, H.K., Salomon, D.S. Cancer Res. (1999) [Pubmed]
  20. Histamine and interleukin-2 in acute myelogenous leukemia. Hellstrand, K., Mellqvist, U.H., Wallhult, E., Carneskog, J., Kimby, E., Celsing, F., Brune, M. Leuk. Lymphoma (1997) [Pubmed]
  21. Differential requirements for cellular cytoskeleton in human macrophage complement receptor- and Fc receptor-mediated phagocytosis. Newman, S.L., Mikus, L.K., Tucci, M.A. J. Immunol. (1991) [Pubmed]
  22. Expression of specific binding sites on Candida with functional and antigenic characteristics of human complement receptors. Edwards, J.E., Gaither, T.A., O'Shea, J.J., Rotrosen, D., Lawley, T.J., Wright, S.A., Frank, M.M., Green, I. J. Immunol. (1986) [Pubmed]
  23. Cripto forms a complex with activin and type II activin receptors and can block activin signaling. Gray, P.C., Harrison, C.A., Vale, W. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  24. IL-10 up-regulates human monocyte phagocytosis in the presence of IL-4 and IFN-gamma. Capsoni, F., Minonzio, F., Ongari, A.M., Carbonelli, V., Galli, A., Zanussi, C. J. Leukoc. Biol. (1995) [Pubmed]
  25. Cripto Binds Transforming Growth Factor {beta} (TGF-{beta}) and Inhibits TGF-{beta} Signaling. Gray, P.C., Shani, G., Aung, K., Kelber, J., Vale, W. Mol. Cell. Biol. (2006) [Pubmed]
  26. Bactericidal/permeability-increasing protein has endotoxin-neutralizing activity. Marra, M.N., Wilde, C.G., Griffith, J.E., Snable, J.L., Scott, R.W. J. Immunol. (1990) [Pubmed]
  27. Requirement of glycosylphosphatidylinositol anchor of Cripto-1 for trans activity as a Nodal co-receptor. Watanabe, K., Hamada, S., Bianco, C., Mancino, M., Nagaoka, T., Gonzales, M., Bailly, V., Strizzi, L., Salomon, D.S. J. Biol. Chem. (2007) [Pubmed]
  28. Growth factor induction of Cripto-1 shedding by glycosylphosphatidylinositol-phospholipase D and enhancement of endothelial cell migration. Watanabe, K., Bianco, C., Strizzi, L., Hamada, S., Mancino, M., Bailly, V., Mo, W., Wen, D., Miatkowski, K., Gonzales, M., Sanicola, M., Seno, M., Salomon, D.S. J. Biol. Chem. (2007) [Pubmed]
  29. Gene expression profiles of hepatoma cell line BEL-7402. Liu, L.X., Jiang, H.C., Liu, Z.H., Zhu, A.L., Zhou, J., Zhang, W.H., Wang, X.Q., Wu, M. Hepatogastroenterology (2003) [Pubmed]
  30. Comparative phenotypic studies of duct epithelial cell lines derived from normal human pancreas and pancreatic carcinoma. Liu, N., Furukawa, T., Kobari, M., Tsao, M.S. Am. J. Pathol. (1998) [Pubmed]
  31. Germ Cell Nuclear Factor Is a Repressor of CRIPTO-1 and CRIPTO-3. Hentschke, M., Kurth, I., Borgmeyer, U., H??bner, C.A. J. Biol. Chem. (2006) [Pubmed]
  32. Systemic suppression of human peripheral blood phagocytic leukocytes after whole-body UVB irradiation. Leino, L., Saarinen, K., Kivistö, K., Koulu, L., Jansen, C.T., Punnonen, K. J. Leukoc. Biol. (1999) [Pubmed]
  33. Allogeneic hematopoietic cell transplantation for patients with high-risk acute lymphoblastic leukemia in first or second complete remission using fractionated total-body irradiation and high-dose etoposide: a 15-year experience. Jamieson, C.H., Amylon, M.D., Wong, R.M., Blume, K.G. Exp. Hematol. (2003) [Pubmed]
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