Cripto Enhances the Tyrosine Phosphorylation of Shc and Activates Mitogen-activated Protein Kinase (MAPK) in Mammary Epithelial Cells

Kannan, Sivakumar; Santis, Marta De; Lohmeyer, M.; Riese, David J.; Smith, Gilbert H.; Hynes, Nancy E.; Seno, Masaharu; Brandt, Ralf; Bianco, Caterina; Persico, Graziella; Kenney, Nicholas; Normanno, Nicola; Martínez-Lacaci, Isabel; Ciardiello, Fortunato; Stern, David F.; Gullick, William J.; Salomon, David

doi:10.1074/jbc.272.6.3330

Cited by 93 publications

(88 citation statements)

References 35 publications

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“…Two separate assays, mammosphere formation and milk protein expression, showed that overexpression of Cr-1 led to decreased differentiation. In agreement with our data, a 47-mer, containing the EGF-like motif only of recombinant human CR-1 is able to stimulate proliferation and inhibit b-casein expression in mouse HC11 mammary epithelial cells (Kannan et al, 1997). It is generally accepted that proliferation rates are inversely related to differentiation, and we demonstrated here that Cr-1 stimulated the proliferation needed to bring the cells to the state required (equivalent to pregnancy) for differentiation (lactation) but inhibited the differentiation process itself.…”

Section: Discussionsupporting

confidence: 80%

Cripto: roles in mammary cell growth, survival, differentiation and transformation

1998

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Cripto-1 (Cr-1) protein, encoded by the teratocarcinomaderived growth factor gene (TDGF-1), is highly correlated with transformation in breast cancer. Eighty-two percent of breast carcinomas express Cr-1 whereas it is undetected in normal human breast tissue. We confirmed and extended findings that Cr-1 protein is expressed during the pregnancy and lactating stages of normal murine mammary glands but is barely detectable in glands from virgin animals and is undetectable in involuted glands. Cr-1 was found to be expressed in CID 9 cells, a line of mammary epithelial cells derived from 14.5 day pregnant mice and we have used these cells to investigate the roles of this gene. 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. CID 9 cells overexpressing Cr-1 did not differentiate efficiently. 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. 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. In transplantation studies, Cr-1 over-expression stimulated the growth and survival of mammary cells, but did not stimulate tumorigenesis in vivo.

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Section: Discussionsupporting

confidence: 80%

Cripto: roles in mammary cell growth, survival, differentiation and transformation

1998

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“…Our lab has previously demonstrated that CR-1 can activate the ras/raf/MAPK and PI3-K/AKT/GSK-3b signaling pathways Kannan et al, 1997;Ebert et al, 1999;Bianco et al, 2004). Interestingly, activation of these signaling pathways can be achieved with a soluble GPI-truncated CR-1 recombinant protein Bianco et al, 2002b).…”

Section: Glypican-1/c-src/mapk/akt Signaling Pathwaymentioning

confidence: 99%

Cripto-1: a multifunctional modulator during embryogenesis and oncogenesis

et al. 2005

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It is increasingly evident that genes known to perform critical roles during early embryogenesis, particularly during stem cell renewal, pluripotentiality and survival, are also expressed during the development of cancer. In this regard, oncogenesis may be considered as the recapitulation of embryogenesis in an inappropriate temporal and spatial manner. The epidermal growth factor-Cripto-1/FRL1/cryptic family of proteins consists of extracellular and cell-associated proteins that have been identified in several vertebrate species. During early embryogenesis, epidermal growth factor-Cripto-1/FRL1/ cryptic proteins perform an obligatory role as coreceptors for the transforming growth factor-beta subfamily of proteins, which includes Nodal. Cripto-1 has also been shown to function as a ligand through a Nodal/Alk4-independent signaling pathway that involves binding to glypican-1 and the subsequent activation through src of phosphoinositol-3 kinase/Akt and ras/mitogen-activated protein kinase intracellular pathways. Expression of Cripto-1 is increased in several human cancers and its overexpression is associated with the development of mammary tumors in mice. Here, we review the role of Cripto-1 during embryogenesis, cell migration, invasion and angiogenesis and how these activities may relate to cellular transformation and tumorigenesis. We also briefly discuss evidence suggesting that Cripto-1 may be involved in stem cell maintenance.

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“…17 ± 20 With respect to intracellular signaling, CR-1 is able to activate the ras/raf/ MEK/MAPK and the PI3-kinase signaling pathways. 9,11,13 In this regard, the activation of p21 ras and PI3-kinase has been linked to the ability of CR-1 to inhibit the expression of b-casein and WAP in mouse mammary HC11 epithelial cells and in primary cultures of midpregnant mouse mammary epithelial cells. 9 The present study was designed to ascertain if CR-1 might modulate apoptosis in HC-11 mouse mammary epithelial cells under conditions where b-casein expression is inhibited.…”

Section: Introductionmentioning

confidence: 99%

“…However, unlike other EGF-like proteins, the human CR-1 protein lacks a conventional hydrophobic signal peptide and transmembrane domain and the modified EGF-like motif which is also possessed by other members of the EGF-CFC family, lacks the A loop, while the B loop is truncated. 13 Another feature that distinguishes CR-1 from other EGF-like peptides is the failure of CR-1 to directly bind to any of the known c-erb-B type 1 receptor tyrosine kinases. 13 However, CR-1 can indirectly induce a transient increase in the tyrosine transphosphorylation of cerb-B 4 in mouse and human mammary epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

“…13 Another feature that distinguishes CR-1 from other EGF-like peptides is the failure of CR-1 to directly bind to any of the known c-erb-B type 1 receptor tyrosine kinases. 13 However, CR-1 can indirectly induce a transient increase in the tyrosine transphosphorylation of cerb-B 4 in mouse and human mammary epithelial cells. 14 CR-1 can inhibit b-casein and whey acidic protein (WAP) expression in vitro in mouse mammary epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

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Cripto-1 induces apoptosis in HC-11 mouse mammary epithelial cells

Santis

Martínez-Lacaci²,

Bianco³

et al. 2000

Cell Death Differ

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Cripto-1 (CR-1) is an epidermal growth factor (EGF)-related protein. CR-1 can inhibit b-casein and whey acidic protein expression in mouse mammary epithelial cells. The present study demonstrates that CR-1 can induce apoptosis in HC-11 mouse mammary epithelial cells, as measured by bisbenzimide stained nuclei, TUNEL assay and cell death ELISA. Apoptosis could be observed after 2 days of exposure of confluent HC-11 cells to CR-1 in the absence of the survival factors EGF and insulin, with maximum apoptosis occurring at 3 days. A reduction in poly(ADP-ribose) polymerase (PARP) expression and an increase in b-catenin cleavage was found after 18 h of exposure to CR-1 suggesting that apoptosis was preceded by the induction of a caspase activity since the caspase inhibitor ZFAD.FMK could block the CR-1-induced reduction in PARP expression and CR-1-induced apoptosis. CR-1 was found to increase the expression of caspase-3-like protease. Although, the levels of p27 kip1 and p21Bax did not change after exposure to CR-1 for 18 h, the levels of Bcl-x L became undetectable. These studies suggest that CR-1 promotes apoptosis by mediating the induction of caspase-3-like protease and downregulating the expression of Bcl-x L .

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Cripto Enhances the Tyrosine Phosphorylation of Shc and Activates Mitogen-activated Protein Kinase (MAPK) in Mammary Epithelial Cells

Cited by 93 publications

References 35 publications

Cripto: roles in mammary cell growth, survival, differentiation and transformation

Cripto: roles in mammary cell growth, survival, differentiation and transformation

Cripto-1: a multifunctional modulator during embryogenesis and oncogenesis

Cripto-1 induces apoptosis in HC-11 mouse mammary epithelial cells

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