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

Santis, M. L. De; Martínez-Lacaci, Isabel; Bianco, Caterina; Seno, Masaharu; Wallace-Jones, Brenda; Kim, N; Ebert, Andreas D.; Wechselberger, Christian; Ds, Salomon

doi:10.1038/sj.cdd.4400588

Cited by 16 publications

(12 citation statements)

References 42 publications

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“…Similar to our results with EGF, heregulin also enhanced the degradation of PARP but unlike EGF, heregulin activated caspase 9 without any significant activation of caspase 3 (51). Cripto-1 mediates the induction of caspase 3-like protease and downregulates the expression of Bcl-XL (15). UCVA-1 cells, derived from human pancreas adenocarcinoma, have a high number of EGFRs but their growth is not inhibited by EGF, highlighting the complexity of the mechanisms involved in EGF-induced apoptosis (52).…”

Section: Discussionmentioning

confidence: 99%

“…Growth factors other than EGF such as platelet-derived growth factor and hepatocyte growth factor can also trigger cell cycle arrest and death in a variety of cells (13,14) and in addition, EGF enhanced the apoptotic effect of platelet-derived growth factor (14). An EGF-related protein, Cripto-1, promotes apoptosis in HC-11 mouse mammary epithelial cells (15). Anoikis, activation of EGFR tyrosine kinase, Ras-MAP kinase signaling, and the elevation of Stat1 and p21 levels have been advocated as mechanisms driving EGF-induced apoptosis (11, 16 -18) but, the actual mechanism appears to be more elusive and complicated.…”

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confidence: 99%

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Inhibition of NF-κB Sensitizes A431 Cells to Epidermal Growth Factor-induced Apoptosis, whereas Its Activation by Ectopic Expression of RelA Confers Resistance

Anto

Manickam²,

Karunagaran

2003

Journal of Biological Chemistry

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Epidermal growth factor (EGF) is a well known mitogen, but it paradoxically induces apoptosis in cells that overexpress its receptor. We demonstrate for the first time that the EGF-induced apoptosis is accelerated if NF-B is inactivated. To inactivate NF-B, human epidermoid carcinoma cells (A431) that overexpress EGF receptor were stably transfected with an IB-␣ double mutant construct. Under the NF-B-inactivated condition, A431 cells were more sensitive to EGF with decreased cell viability and increased externalization of phosphatidylserine on the cell surface, DNA fragmentation, and activation of caspases (3 and 8 but not 9), typical features of apoptosis. These results were further supported by the potentiation of the growth inhibitory

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibition of NF-κB Sensitizes A431 Cells to Epidermal Growth Factor-induced Apoptosis, whereas Its Activation by Ectopic Expression of RelA Confers Resistance

Anto

Manickam²,

Karunagaran

2003

Journal of Biological Chemistry

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“…The elucidation of the signals and transcriptional events underlying the up-regulation of Cripto expression in these tumors remains an important area of future research. With regard to Cripto's mechanism(s) of action, it has been shown that recombinant, soluble Cripto can activate both the p42 mitogen-activated protein kinase pathway (40) and the phosphatidylinositol 3-kinase pathway (41) in mammary epithelial cells through an unidentified receptor. The ability of Cripto to activate these pathways, which are frequently growth-stimulatory in nature, may at least partially explain its effects on cell growth, differentiation, and oncogenesis (17).…”

Section: Discussionmentioning

confidence: 99%

Cripto forms a complex with activin and type II activin receptors and can block activin signaling

Gray

Harrison

Vale

2003

Proc. Natl. Acad. Sci. U.S.A.

149

126

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Activin, nodal, Vg1, and growth and differentiation factor 1 are members of the transforming growth factor ␤ superfamily and signal via the activin type II (ActRII͞IIB) and type I (ALK4) serine͞ threonine kinase receptors. Unlike activins, however, signaling by nodal, Vg1, and growth and differentiation factor 1 requires a coreceptor from the epidermal growth factor-Cripto-FRL1-Cryptic protein family such as Cripto. 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. Because Cripto mediates signaling via activin receptors and binds directly to ALK4, we tested whether transfection with Cripto would affect the ability of activin to signal and͞or interact with its receptors. Here we show that Cripto can form a complex with activin and ActRII͞IIB. We were unable to detect activin binding to Cripto in the absence of ActRII͞IIB, indicating that unlike nodal, activin requires type II receptors to bind Cripto. If cotransfected with ActRII͞IIB and ALK4, Cripto inhibited crosslinking of activin to ALK4 and the association of ALK4 with ActRII͞IIB. In addition, Cripto blocked activin signaling when transfected into either HepG2 cells or 293T cells. We have also shown that under conditions in which Cripto facilitates nodal signaling, it antagonizes activin. Inhibition of activin signaling provides an additional example of a Cripto effect on the regulation of signaling by transforming growth factor-␤ superfamily members. Because activin is a potent inhibitor of cell growth in multiple cell types, these results provide a mechanism that may partially explain the oncogenic action of Cripto.

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“…This may be the case since we have found recently that CR-1 can induce apoptosis in several nontransformed mouse mammary epithelial cell lines. Apoptosis could be observed after 2 days exposure of confluent HC-11 cells to CR-1 when cells were deprived of the survival factors, EGF and insulin (De Santis et al 2000). Apoptosis was mediated through the induction of a caspase-3-like protease and down-regulation in the expression of the anti-apoptotic protein Bcl-x L .The induction of apoptosis under reduced serum by CR-1 was preceded by an inhibition in cell growth and a reduction in poly(ADP-ribose) polymerase (PARP) protein and an increase in β-catenin cleavage.…”

Section: In Vitro Effects Of Transduced Cr-1 or Recombinant Cr-1 In Mmentioning

confidence: 99%

“…Apoptosis was mediated through the induction of a caspase-3-like protease and down-regulation in the expression of the anti-apoptotic protein Bcl-x L .The induction of apoptosis under reduced serum by CR-1 was preceded by an inhibition in cell growth and a reduction in poly(ADP-ribose) polymerase (PARP) protein and an increase in β-catenin cleavage. A reduction in β-catenin levels due to caspase-3-mediated degradation may result in a loss of cell-cell and cell-matrix interactions with an increase in anoikis (De Santis et al 2000). Cr-1 has also been demonstrated to act as a survival factor in CID-9 cells transfected with a Cr-1 expression vector when cells were propagated under sparse, subconfluent conditions in medium containing low serum and insulin (Niemeyer et al 1998).…”

Section: In Vitro Effects Of Transduced Cr-1 or Recombinant Cr-1 In Mmentioning

confidence: 99%

The EGF-CFC family: novel epidermal growth factor-related proteins in development and cancer.

Saloman

Bianco

Ebert

et al. 2000

Endocrine-Related Cancer

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123

112

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The EGF-CFC gene family encodes a group of structurally related proteins that serve as important competence factors during early embryogenesis in Xenopus, zebrafish, mice and humans. This multigene family consists of Xenopus FRL-1, zebrafish one-eyed-pinhead (oep), mouse cripto (Cr-1) and cryptic, and human cripto (CR-1) and criptin. FRL-1, oep and mouse cripto are essential for the formation of mesoderm and endoderm and for correct establishment of the anterior/ posterior axis. In addition, oep and cryptic are important for the establishment of left-right (L/R) asymmetry. In zebrafish, there is strong genetic evidence that oep functions as an obligatory co-factor for the correct signaling of a transforming growth factor-β (TGFβ)-related gene, nodal, during gastrulation and during L/R asymmetry development. Expression of Cr-1 and cryptic is extinguished in the embryo after day 8 of gestation except for the developing heart where Cr-1 expression is necessary for myocardial development. In the mouse, cryptic is not expressed in adult tissues whereas Cr-1 is expressed at a low level in several different tissues including the mammary gland. In the mammary gland, expression of Cr-1 in the ductal epithelial cells increases during pregnancy and lactation and immunoreactive and biologically active Cr-1 protein can be detected in human milk. Overexpression of Cr-1 in mouse mammary epithelial cells can facilitate their in vitro transformation and in vivo these Cr-1-transduced cells produce ductal hyperplasias in the mammary gland. Recombinant mouse or human cripto can enhance cell motility and branching morphogenesis in mammary epithelial cells and in some human tumor cells. These effects are accompanied by an epithelial-mesenchymal transition which is associated with a decrease in β-catenin function and an increase in vimentin expression. Expression of cripto is increased several-fold in human colon, gastric, pancreatic and lung carcinomas and in a variety of different types of mouse and human breast carcinomas. More importantly, this increase can first be detected in premalignant lesions in some of these tissues. Although a specific receptor for the EGF-CFC proteins has not yet been identified, oep depends upon an activin-type RIIB and RIB receptor system that functions through Smad-2. Mouse and human cripto have been shown to activate a ras/raf/MAP kinase signaling pathway in mammary epithelial cells. Activation of phosphatidylinositol 3-kinase and Akt are also important for the ability of CR-1 to stimulate cell migration and to block lactogenic hormone-induced expression of β-casein and whey acidic protein.In mammary epithelial cells, part of these responses may depend on the ability of CR-1 to transactivate erb B-4 and/or fibroblast growth factor receptor 1 through an src-like tyrosine kinase.

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

Cited by 16 publications

References 42 publications

Inhibition of NF-κB Sensitizes A431 Cells to Epidermal Growth Factor-induced Apoptosis, whereas Its Activation by Ectopic Expression of RelA Confers Resistance

Inhibition of NF-κB Sensitizes A431 Cells to Epidermal Growth Factor-induced Apoptosis, whereas Its Activation by Ectopic Expression of RelA Confers Resistance

Cripto forms a complex with activin and type II activin receptors and can block activin signaling

The EGF-CFC family: novel epidermal growth factor-related proteins in development and cancer.

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