The human cripto-1 (CR-1) gene ( also known as teratocarcinoma-derived growth factor-1 [TDGF-1] ) is located on chromosome 3p21 and codes for a 28- to 36-kDa glycoprotein of 188 amino acids that lacks a conventional hydrophobic signal peptide and transmembrane domain. CR-1 possesses an epidermal growth factor (EGF)-like consensus sequence that contains six cysteine residues in a region of approximately 37 amino acids (1). However, unlike other peptides within the EGF family that have a three-looped EGF-motif (designated A, B, and C), the EGF-like repeat in CR-1 lacks an A loop while the B loop is truncated. Refolded CR-1 peptides that correspond to the EGF-like repeat within the human CR-1 protein are mitogenic for nontransformed and malignant mouse and human mammary epithelial cells (2). CR-1 refolded peptides do not bind to the EGF receptor nor do they directly activate the c-erb B-2, c-erb B-3, or c-erb B-4 type 1 receptor tyrosine kinases. Exogenous CR-1 can also modify the expression of milk proteins such as b-casein and WAP in response to prolactin, insulin and glucocorticoids in mouse HC-11 mammary epithelial cells and in primary mouse mammary explant cultures from midpregnant mice (Kannan et. al. manuscript submitted for publication). In addition, CR-1 can induce branching morphogenesis when NMuMG mouse mammary epithelial cells are maintained in type 1 collagen gells due to a modification in the expression and association of different cell adhesion proteins that are present in the adherens junctions. CR-1 has been found to interact with a high affinity, saturable receptor that exhibits specificity for CR 1. Exogenous CR-1 has also been found to induce a rapid and transient increase in the tyrosine phosphorylation of the SH2-containing adaptor protein Shc and an increase in the association of the Grb2- guanine nucleotide exchange factor SOS signalling complex with phosphorylated Shc ( Kannan et. al., manuscript submitted for publication ). CR-1 can also increase mitogen-activated protein kinase (MAPK) activity . CR-1 is normally expressed in the cap stem cells of the growing terminal end buds in the virgin mouse mammary gland and expression of CR-1 is increased in a subpopulation of ductal epithelial cells in the mammary gland during pregnancy and lactation (3). Human or mouse CR-1 can also function as a dominant transforming genes in vitro in mouse NIH-3T3 fibroblasts and in mouse NOG-8 mammary epithelial cells (4). This may have in vivo significance since overexpression of CR-1 in primary mouse mammary epithelial cells can lead to an increase in ductal growth and branching and to the eventual clonal expansion of ductal hyperplasias when CR-1 transduced mammary epithelial cells are subsequently transplanted into the cleared mammary fat pad of virgin, ovariectomized, syngeneic mice (N. Kenney et. al., manuscript in preparation ). In addition, CR-1 mRNA and immunoreactive CR-1 protein are expressed in mammary tumors that develop at a high frequency in several different types of transgenic mice, in approximately 80% of primary human breast tumors and in 50% of ductal carcinomas in situ (5,6). In contrast, only 15% of adjacent and noninvolved mammary epithelium or non-breast cancer samples are positive for CR-1 expression where the level of expression is generally lower than in carcinoma cells. Generation of CR-1 transgenic mice using regulatory elements that are expressed in the mammary gland during different developmental stages such as the MT-1, MMTV and WAP promoters and selective inactivation of the CR-1 locus in the mammary gland to generate a homozygous deletion using the Cre-lox P recombination system should help to clarify the importance of this novel gene in mammary gland development and neoplasia. Nevertheless, the ability of CR-1 to bind to a novel tyrosine kinase receptor and to subsequently modulate ductal morphogenesis and the expression of different milk protein genes suggests that CR-1 performs a significant biological function in the mammary gland and that inappropriate overexpression of CR-1 may contribute to the early stages of mammary tumorigenesis.
Growth, morphogenesis, and lactation in the mammary gland is regulated by a complex interplay of systemic ovarian and pituitary hormones and locally-derived growth factors that are expressed either in the mammary stroma (e.g. hepatocyte growth factor[HGF], fibroblast growth factor-2[FGF-2]/basic FGF, keratinocyte growth factor[KGF]/FGF-7, heregulin [HRG]a, transforming growth factor b[TGFb], insulin-like growth factors) or in the epithelium (e.g. EGF, transforming growth factor a [TGFa], amphiregulin [AR], FGF-1/acidic FGF) at defined periods during mammary gland development. In this context, EGF and some other related peptide growth factors in this large superfamily of proteins which includes TGFa, AR, heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), epiregulin (EP) and the neuregulin subfamily that consists of various isoforms of a and b HRG, gilial cell growth factors (GGFs), sensory motor neuron-derived growth factor (SMDGF) and acetycholine receptor-inducing activity (ARIA) are important modulators of mammary epihelial cell growth and differentiation (rf. Table 1)(7). For example, EGF,AR and TGFa are expressed in the virgin mouse mammary gland in either ductal epithelial cells or in the cap stem cells of the terminal end buds whereas HRGa expression is generally restricted to a subpopulation of mesenchymal cells in the mammary gland during pregnancy and lactation(8). In addition, when implanted in Elvax pellets both EGF,TGFa and to a lesser extent AR can induce in vivo longitudinal ductal growth and lobulo-alveolar development in the mammary gland of ovariectomized virgin mice following estrogen and progesterone priming(9). However, in hormonally competent mice EGF actually inhibits ductal growth. These peptides can also modify differentiation. For example, in primary mouse mammary epithelial cell cultures or in mouse mammary gland explant cultures supplemented with insulin and hydrocortisone, growth factors such as EGF, TGFa or various HRGb isoforms can either stimulate or inhibit the expression of the milk proteins, b-casein and WAP, depending upon the presence or absence of prolactin and depending upon whether the mammary epithelial primary cultures or explants were initiated from mammary glands that were obtained from either virgin or pregnant mice(10). The role of other EGF-related growth factors in regulating the differentiation of mammary epithelial cells has not been fully explored. This may be particularly important since only a subset of peptides within the EGF family bind exclusively to the epidermal growth factor receptor (erb B/EGFR). Additional proteins in this family such as the neuregulin subfamily bind to other members of the type 1 receptor tyrosine kinase family of receptors such as c-erb B-3 or c-erb B-4 that can then heterodimerize and activate c-erb B-2 ,which has as of yet no known ligand, following transphosphorylation. Finally, BTC can simultaneously activate either the EGFR or c-erb B-4 . Since ligand-dependent activation of the EGF receptor can also lead to heterodimerization with either c-erb B-2, c-erb B-3, or c-erb B-4, this suggests that different pairs of heterodimers within the type 1 receptor tyrosine kinase family may contribute to the array of responses to various EGF-like ligands in a cell-specific and possibly ligand-specific manner by the recruitment of different combinations of intracellular signalling proteins in the ras/raf/MEKK/MAPK pathway and/or possibly by modification of members in the JAK/STAT pathway(11).
Additional levels of control exist for these growth factors and their cognate receptors. For example, TGFa and AR are overexpressed at a high frequency in a majority of primary human breast carcinomas and in a number of human breast cancer cell lines. The EGFR is also overexpressed due to transcriptional upregulation in a subpopulation of human breast carcinomas that predominantly are estrogen receptor (ER) negative whereas erb B-2 is overexpressed in approximately 20-30% of human breast carcinomas due in most cases to gene amplification(12). Overexpression of TGFa or HRGb2 are the only EGF-related peptides to date that have been formally demonstrated to contribute to the malignant transformation of either mouse or human mammary epithelial cells either in vitro orin vivo in transgenic mice using either MMTV or MT-1 promoter driven expression constructs(13). Reciprocally, mammary epithelial cells in vitro or transgenic mice that are expressing oncogenes such as a point-mutated c-Ha-ras gene or overexpressed c-erb B-2 gene become transformed and develop mammary tumors. These mammary carcinoma cells exhibit elevated expression of TGFa, AR and/or HRG. Expression of TGFa, AR, EGFR, erb B-2 and erb B-3 can also be enhanced (TGFa, AR and EGFR ) or inhibited (erb B-2 and erb B-3) by estrogens through a transcriptional regulated, ER-dependent pathway in ER positive human breast cancer cell lines. Antiestrogens such as tamoxifen have opposite effects to estrogen in these responses (e.g. decreasing TGFa expression and elevating erb B-2 expression). The expression of TGFa, AR, HRGa, EGFR and erb B-2 are also elevated during pregnancy and lactation in the mouse mammary gland suggesting that lactational hormones may also be involved in regulating the expression of these proteins. Using EGFR blocking antibodies, growth factor neutralizing antibodies or antisense expression vectors , it has been formally deomonstrated that TGFa and AR may be functioning through the EGFR as estrogen-inducible, autocrine and/or juxtacrine growth factors to drive normal and malignant mammary epithelial cell proliferation(14,15).
A novel EGF-related gene that encodes a peptide growth factor, Cripto-1 (CR-1) ( also
known as terataocarcinoma-derived growth factor-1[TDGF-1]) was serendipitously isolated
and sequenced from a human embryonal carcinoma cDNA library(1). Homologous genes have
subsequently been identified in the mouse (Tdgf-1) and in Xenopus laevis (FRL1)(16,17).
Human CR-1/TDGF-1 maps adjacent to a region on chromosome 3p21.3 that is frequenlty
deleted or exibits loss of heterozygosity in a subpopulation of renal, breast and
non-small cell lung carcinomas and that is distal to the Wnt5A locus. The mouse (Tdgf-1)
and human (CR-1/TDGF-1) genes consist of six exons and five introns and possess inverted
Alu sequence elements and AUUU(A)-type Kamen-like sequences in a large 3' untranslated
region. Exon 4 codes for the EGF-like motif (16,18). At least five other human CR-1/TDGF-1
genes and two additional mouse Tdgf-1 related genes have been identified. In this respect,
CR-3/TDGF-3 in the human which maps to the Xq21-q22 region and Tdgf-2 in the mouse are
intronless pseudogenes that have many characteristics of a retroposon but have the
potential to code for proteins that differ from the proteins encoded by either CR-1 or
Tdgf-1 by only five amino acids. The human CR-1 and mouse Tdgf-1 genes encode major mRNA
species of 2.2 kb and in some cases minor species of 1.8 and 3.2 kb that may arise by use
of different polyadenylation signal sequences or by alternative splicing. The human and
mouse CR-1/TDGF-1 and Tdgf-1 genes encode proteins of 188 and 171 amino acids,
respectively that range from 24 to 36 kDa in size after postranslational modification(2).
The human CR-1 protein contains an N-glycosylation site, five potential myristylation
sites , and three consenus sites for potential phosphorylation on serine by protein kinase
C and by cyclic AMP-dependent protein kinase A. Both mouse and human proteins possess an
internal region of approximately 37 amino acids that has a modified EGF-like motif which
can fold into a structure that lacks an A loop, possesses a truncated B loop and has a
complete C loop
Within this EGF-like region there is nearly 93% amino acid sequence identity between the mouse and human proteins. Additionally, both proteins lack a hydrophobic transmembrane domain and human CR-1 unlike mouse Tdgf-1 also lacks a conventional hydrophobic signal peptide.
Expression of CR-1 related genes
Little is known about the expression pattern of CR-1 in adult human tissues. However, in
the mouse low levels of Tdgf-1 mRNA expression can be detected in the adult spleen, heart,
lung and in distinct regions of the brain. During early embryogenesis,Tdgf-1 expression
can first be detected in the mouse blastocyst using RT-PCR(16,19). In this context,
CR-1/TDGF-1 and Tdgf-1 are expressed in undifferentiated human NTERA2/D1 and mouse F9
embryonal carcinoma cells whereas expression is lost in these cells following retinoic
acid-induced differentiation(1). Tdgf-1 expression in the midgestation mouse embryo is
temporally and spatially restricted to the primitive streak and developing mesoderm during
gastrulation and to the myocardium of the truncus arterious in the developing heart at
later stages(16). In Xenopus laevis, a related gene ,FRL1, has been identified and shown
to encode a protein that is 24% homologous overall to mouse Tdgf-1 and human cripto-1(17).
However, the modified EGF-like motif in this protein is completely conserved. Similar to
mouse Tdgf-1 protein, the FRL1 protein contains a signal peptide and an additional unique
modification in the carboxy-terminus suggesting that it is probably membrane-associated.
In Xenopus oocytes and in yeast (S. cerevisiae ) simultaneous ectopic overexpression of
FRL1 and the Xenopus FGF receptor-1 (FGFR-1) leads to Ca2+influx and to the indirect
activation of the FGFR-1 tyrosine kinase. In isolated animal caps from Xenopus embryos,
FRL1 like FGF, activin and the Xwnt-8 gene induces the formation of mesoderm and the
expression of mesoderm related genes. In the case of FRL1, this occurs through an
FGFR-mediated pathway. Overexpression of FRL1 in Xenopus embryos leads to the preferential
development of posterior mesoderm related structures at the expense of anterior head
structures. FRL1 expression in Xenopus is only detected during gastrulation and during the
early stages of neurulation.
A first clue to the biological activity that might be associated with this EGF-related subfamily of genes in mammals was gleamed from the ability of human CR-1 to transform mouse NIH/3T3 fibroblasts and mouse NOG-8 mammary epithelial cells in vitro when the gene was overexpressed in these cells (rf. Table 2). However, NOG-8 transformants were unable to form tumors in nude mice suggesting that additional genetic alterations were necessary to complete the tumorigenic phenotype in vivo (4). Conversely, in CREF rat embryo fibroblasts that have been transformed by an activated c-Ha-ras protooncogene expression of ratTdgf-1 is substantially upregulated (20). This may have in vivo significance since overexpression of the mouse Tdgf-1 gene in primary FVB/N or C57Bl/6 mouse mammary epithelial cells can lead to an increase in lateral ductal branching and to the clonal expansion of mammary hyperplasias after these transduced cells are reintroduced into the cleared mammary fat pad of syngeneic, ovariectomized virgin mice (Kenney et. al., manuscript in preparation). Likewise, insertion of Elvax pellets containing a human 47-mer CR-1 related, refolded peptide that corresponds in sequence to the EGF-like motif into the mammary gland of ovariectomized, virgin mice can result in an increase in ductal branching surrounding these pellets. A similar in vitro related effect has been observed with this p47 CR-1 peptide in mouse NMuMG mammary epithelial cells in type 1 collagen gels in vitro where branching morphogenesis can be induced through changes in the expression of b catenin and in the interaction of b catenin with E-cadherin and a catenin in adhesion plaque junctions (De Santis et. al., manuscript in preparation). Tdgf-1 expression in the developing mouse mammary gland has been examined by using RT-PCR, immunocytochemistry and Western blot analysis. Different levels ofTdgf-1 expression were detected in the virgin, pregnant and lactating mammary gland. In the virgin mammary gland, expression was observed primarily but not exclusively in the cap stem cells of the growing terminal end buds and in the ductal epithelial cells in the mammary gland from pregnant and lactating mice(3). Expression of Tdgf-1 in ductal epithelial cells was enhanced by several fold during pregnancy and lactation and in the aging (24 month) mammary gland of multiparous Balb/c mice which exhibit a high incidence of spontaneous mammary tumor development. In this regard, a majority of carcinoma cells in spontaneous mouse mammary tumors and in mammary tumors that arise in transgenic mice which are overexpressing different genes such as TGFa, c-neu, int-3 , polyoma middle t or SV40 large T in the mammay gland also overexpress different isoforms of the Tdgf-1 protein at a high frequency relative to the surrounding noninvolved mammary epithelium(21). Collectively, these data suggest that Tdgf-1 might function as an epithelial cell-derived autocrine growth factor and/or morphogen in the developing mammary gland and that chronic and inappropriate overexpression of Tdgf-1 may contribute to the onset of neoplasia in the mouse mammary gland. These data may be clinically relevant to the pathogenesis of human breast cancer. Low levels of human CR-1 protein and mRNA expression have been detected in several human breast cancer cell lines (MCF-7, T47-D, ZR-75-1,MDA-MB-231 and MDA-MB-468). More importantly, CR-1 expression has been collectively assessed in four separate studies in 254 infiltrating (IDC) or intralobular (ILC) carcinomas and in 55 ductal carcinomas in situ (DCIS) and compared to the relative level of expression in noninvolved, adjacent mammary epithelium. Approximately 80% of IDC or ILC and 50% of DCIS specimens stained moderately to intensely for CR-1 expression in over 60% of the tumor cells compared to only 15% of the specimens of noninvolved mammary epithelial cells where less than 20% of the cells stained weakly(5,6,22). These values compared favorably with the frequency of CR-1 mRNA expression in these samples as detected by RT-PCR analysis. No significant correlations were observed between CR-1 mRNA expression or immunoreactivity and various clinicopathological parameters such as steroid receptor status, EGFR status or axillary lymph node involvement. Although the functional role or significance of CR-1 overexpression in breast tumors is unclear, suppression of CR-1 expression in GEO or CBS human colon carcinoma cells and in NTERA2/D1 embryonal carcinoma cells has been achieved after treatment of these cells with either CR-1 antisense phosphorothioate oligodeoxynucleotides or after infection with a recombinant CR-1 antisense retroviral expression vector (23,24). Reduced CR-1 expression in these cells resulted in an inhibition in the anchorage-dependent and anchorage-independent growth of these cells in vitro and lengthened the latency period and decreased the number of tumors in vivo in nude mice in transduced antisense expressing carcinoma cells. A full-length, refolded recombinant mouse or human CR-1 protein has yet to be purified in sufficient quantities to execute a number of biological studies. Nevertheless, transient expression of either human or mouse CR-1 in CHO cells has demonstrated that both proteins can be effectively secreted either as 28 or 24 kDa immunoreactive glycoproteins, respectively(2). Treatment of these cells with tunicamycin or treatment of cell lysates or conditioned medium (CM) with N-glycanase resulted in a shif in the size of these proteins to approximately 20 kDa, the expected size of the core protein. The native human protein that is expressed in colon and embryonal carcinoma cells is approximately 36 kDa suggesting that additional glycosylation or other posttranslational modifications can occur. This protein has a tendency to associate with the Golgi or plasma membrane fraction. CM from CHO clones that are expressing human CR-1 has the ability to moderately stimulate the proliferation of serum-starved nontransformed human mammary epithelial cells (184A1N4) and some human breast cancer cell lines (SKBr-3 and MDA-MB-453). Since sufficient amounts of this recombinant protein from the CM of CHO cells were not available, a refolded 47-mer CR-1 peptide that contains the modified EGF-like motif was utilized and found to produce equivalent growth-promoting responses as CM in these same cells. This peptide was unable to bind to the EGFR or to directly activate erb B-2, erb B-3 or erb B-4 type 1 receptor tyrosine kinases that had been ectopically expressed in Ba/F3 mouse pro-B lymphocytes either alone or in various pairwise combinations. Cells that respond to CR-1 were found to possess a specific, high affinity and saturable receptor for CR-1 since other EGF-related peptides that bind to either the EGFR or to erb B-3 or erb B-4 were unable to compete for binding on different CR-1 responsive mouse and human target cells suggesting that this may represent a novel receptor (Kannan et. al., manuscript submitted for publication). Activation of this putative CR-1 receptor in HC-11 mouse mammary epithelial cells can lead to a rapid and transient increase in the tyrosine phosphorylation of the p66 and p46 isoforms of the SH2-SH3 adaptor proteinShc . CR-1 was also found to facilitate the interaction ofShc with the intracellular Grb2-SOS signalling complex which can function as a ras guanine nucleotide exchanger. Finally, CR-1 has subsequently been shown to enhance the downstream tyrosine phosphorylation and activation of the MAPK isoform, p42 erk2 demonstrating that the ras/raf/MEKK/MAPK pathway can be activated by CR-1 directly or indirectly through its receptor. This may be functionally relevant to the type of response that CR-1 can produce in HC-11 cells which express b-casein at confluency after exposure to dexamethasone, insulin and prolactin (DIP). Similar to EGF and other EGF-related peptides that activate the EGFR, pretreatment of HC-11 cells with human CR-1 during log phase growth can enhance the expression of b-casein in response to the subsequent treatment with DIP. Conversely, CR-1 could significantly impair DIP-induced expression of b-casein if HC-11 cells were simultaneously exposed to DIP and CR-1. This inhibitory effect to CR-1 was not unique to this particular cell line since a similar inhibitory effect on b-casein and WAP expression in the presence of DIP was observed to occur in primary mouse mammary explant cultures that were established from 10-day midpregnant mice. These data collectively demonstrate that CR-1 can function as a growth factor but more importantly as a differentiation factor in mammary epithelial cells during ductal morphogenesis and during pregnancy in the regulation of milk protein expression. Elevated expression of CR-1 during pregnancy further supports a potential in vivo role for this cytokine. Identification and characterization of the CR-1 receptor should significantly contribute to our understanding about the function and activity of this family of novel growth factors in the pathophysiology of the mammary gland.
The author wishes to express his gratitude to Drs. Graziella Persico, William J. Gullick, Ralf Brandt, Subha Kannan, Nicholas Kenney, Fortunato Ciradiello, Nicola Normanno and Marta De Santis for their continued collaborative efforts in this research.
1. Ciccodicola, A., Dono, R., Obici, S., Simeone, A., Zollo, M. & Persico, M. G. (1989) EMBO J. 8, 1987-1991.
2. Brandt, R., Normanno, N., Gullick, W. J., Lin, J.-H., Harkins, R., Schneider, D., Jones, B. W., Ciardiello, F., Persico, M. G., Armenante, F., Kim, N. & Salomon, S. (1994) J. Biol. Chem. 269, 17320-17328.
3. Kenney, N. J., Huang, R.-P., Johnson, G. R., Wu, J.-X., Okamura, D., Matheny, W., Kordon, E., Gullick, W. J., Plowman, G., Smith, G. H., Salomon, D. S. & Adamson, E. D. (1995) Mol. Reprod. Dev. 41, 277-286.
4. Ciardiello, F., Dono, R., Kim, N., Persico, M. G. & Salomon, D. S. (1991) Cancer Res. 51, 1051-1054.
5. Qi, C.-F., Liscia, D. S., Normanno, N., Merlo, G., Johnson, G. R., Gullick, W. J., Ciardiello, F., Saeki, T., Brandt, R., Kim, N., Kenney, N. & Salomon, D. S. (1994) Br. J. Cancer 69, 903-910.
6. Dublin, E. A., Bobrow, L. G., Barnes, D. M. & Gullick, W. J. (1995) Int. J. Oncol. 7, 617-622.
7. Normanno, N., Ciardiello, F., Brandt, R., and Salomon, D.S (1994)Breast Cancer Res. & Treat.. 29,11-27.
8. Yang, Y., Spitzer, E., Meyer, D., Sachs, M., Niemann, C., Hartmann G., Weidner, K. M., Birchmeier, C. & Birchmeier, W. (1995) J. Cell Biol. 131, 215-226.
9. Vonderhaar, B. K. (1988) in Breast Cancer: Cellular and Molecular Biology, eds. Lippman, M. E. & Dickson, R. B. (Kluwer Academic, Boston), pp. 251-266.
10. Spitzer, E., Zschiesche, W., Binas, B., Grosse, R. & Erdmann, B. (1995) J. Cell. Biochem. 57, 495-508.
11. Earp, H. S., Dawson, T. L., Li, X. & Yu, H. (1995) Breast Cancer Res. Treat. 35, 115-132.
12. Salomon, D.S., Brandt, R., Ciardiello, F., and Normanno, N.(1995) Crit. Rev. Oncol. & Hematol. 19, 183-232.
13. Krane, I.M. and Leder, P. (1996) Oncogene. 12,1781-1788.
14. Kenney, N., Saeki, T., Gottardis, M., Garcia-Morales, P., Martin, M.-B., Rochefort, H., Normanno, N., Kim, N., Ciardiello, F., and Salomon, D.S. (1993) J. Cell. Physiol. 156, 497-514.
15. Martinez-Lacaci,I., Saceda, M., Plowman, G.D., Johnson, G.R., Normanno, N., Salomon, D.S. and Dickson, R.B. (1995) Endocrionol. 136, 3983-3992.
16. Dono, R., Scalera,L., Pacifico, F., Acampora, D., Persico, M.G. and Simeone, A. (1993) Development. 118, 1157-1168.
17. Kinoshita, N., Minshull, J. and Kirschner, M.W. (1995) Cell. 83, 621-630.
18. Liguori,G., Tucci, M., Montouri, N., Dono, R., Lago, C.T., Pacifico, F., Aremenante, F. anf Persico, M.G. (1996) Mammalialian Genome. 7, 344-348.
19. Johnson, S.E., Rothstein, J.L. and Knowles, B.B. (1994) Develop. Dynamics. 201, 216-226.
20. Zao-Zhong, S., Austin, V.N., Zimmer, S.G. and Fisher, P.B. (1993) Oncogene. 8, 1211-1219.
21. Kenney, N., Smith, G.H., Maroulakou, I.G., Green, J.H., Muller, W.J., Merlino, G.H., Callahan, R. H., Salomon, D.S. and Dickson, R.B. (1996) Mol. Carcinogenesis. 15,44-56.
22. Pancino,L., D'Antonio,A., Salvatore,G., Mazza,E., Tortora, G., DeLaurentis,M., DePlacido,S., Giordano,T., Merino,M., Salomon, D.S., Gullick, W.J., Pettinato,G., Bianco,R. and Ciardiello,F. (1996) Int. J. Cancer 65, 51-56.
23. Ciardiello, F., Tortora, G., Bianco, C., Selvam, M.P., Basolo, F., Fontanini, G., Pacifico, F., Normanno, N., Brandt, R., Persico, M.G., Salomon, D.S., and Bianco, R.A. (1994) Oncogene 9, 291-298.
24. Baldassarre, G., Bianco, C., Tortora, G., Ruggiero, A., Moasser, M., Dimitovsky, E., Bianco, R.A. and Ciardiello. (1996) Int. J. Cancer. 66, 538-543.
Keywords:
EGF, cripto, morphogenesis, transformationFig. 1
contributed by David S. Salomon
David S. Salomon
Chief, Tumor Growth Factor Section
Laboratory of Tumor Immunology & Biology
NCI, NIH, Bethesda, MD. 20892.
Fax#: 301-402-8656
email: davetgfa@helix.nih.gov
(e-mail davetgfa@helix.nih.gov)
Last update: June 1998 |
