Induction of apoptosis in fibroblasts by c-myc protein

Evan, Gérard I.; Wyllie, Andrew H.; Gilbert, Christopher S.; Littlewood, Trevor D.; Land, Hartmut; Brooks, Mary W.; Waters, Catherine; Penn, Linda Z.; Hancock, David C.

doi:10.1016/0092-8674(92)90123-t

Cited by 2,811 publications

(1,802 citation statements)

References 31 publications

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“…17,48 In several independent experiments, Myc-induced apoptosis was increased approximately two-fold by the loss of MIF and was alleviated on the p53 null background (Figure 5b). Similar results were obtained using cyclin-dependent kinase 4 (CDK4)-and E2F1-transduced fibroblasts (Figure 5b).…”

Section: Loss Of Mif Enhances P53-and E2f1-mediated Apoptosismentioning

confidence: 92%

MIF loss impairs Myc-induced lymphomagenesis

et al. 2005

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Macrophage migration inhibitory factor (MIF) is a potent regulator of inflammation and cell growth. Using the El-Myc lymphoma mouse model, we demonstrate that loss of MIF markedly delays the onset of B-cell lymphoma development in vivo. The molecular basis for this MIF-loss-induced phenotype is the perturbed DNA-binding activity of E2F factors and the concomitantly enhanced tumor suppressor activity of the p53 pathway. Accordingly, premalignant MIF-null El-Myc Bcells are predisposed to delayed S-phase progression and increased apoptosis. MIF-deficient lymphomas that do arise under these conditions contain frequent ARF deletions and p53 inactivating mutations. Conversely, MIF expression is retained in tumors developed by wild-type El-Myc animals, and the presence of one or both MIF alleles is sufficient to accelerate the development of Myc-induced lymphomas. Collectively, these results indicate that MIF promotes Mycmediated tumorigenesis, at least in the B-lymphoid compartment, and implicate MIF as a mediator of malignant cell growth in vivo.

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Section: Loss Of Mif Enhances P53-and E2f1-mediated Apoptosismentioning

confidence: 92%

MIF loss impairs Myc-induced lymphomagenesis

et al. 2005

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“…Inducible expression of activated MEKK stimulated the transactivation of cMyc and Elk-1 (Johnson et al, 1996). To date, molecules involved in signaling apoptosis include ceramide (Jimenez et al, 1995), Rho, Ras, c-Myc, p53, E1A (Canman and Kastan, 1995), c-Jun (Evan et al, 1992), Fas (Wang et al, 1994), proteins associated with the TNFa receptor (Chinnaiyan et al, 1995), BRCA1 ), Fos (Preston et al, 1996, E2F-1 (Shan et al, 1996), c-Myc and c-Jun transcription factors which are regulated by MAPK phosphorylation also induce apoptosis (Canman and Kastan, 1995). Since Elk-1 protein regulates c-Fos oncogene and is a target for MAPK and JNK both of which are activated by MEKK, we speculated whether it could play a similar role in inducing an apoptotic response.…”

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confidence: 99%

“…Thus Elk-1 and DElk-1 proteins induce apoptosis similar to Rho, Ras, c-Myc, c-jun, Fas, BRCA1, Fos, p53, E1A, E2F-1, etc (Canman and Kastan, 1995;Evan et al, 1992;Wang et al, 1994;Shao et al, 1996;Preston et al, 1996;Shan et al, 1996). The precise mechanism by which Elk-1 induces cell death remains to be investigated.…”

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confidence: 99%

Induction of apoptosis by Elk-1 and ΔElk-1 proteins

et al. 1998

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Elk-1, an ets related gene codes for at least two splice variants Elk-1, which regulates c-fos transcription and DElk-1, both of which function as transcriptional activators. To investigate the role of Elk-1 and DElk-1 proteins in apoptosis; we have developed rat ®broblast cell lines and human breast cancer cell lines expressing Elk-1 and DElk-1. The expression of Elk-1 and DElk-1 proteins in the Elk-1/DElk-1 transfectants were analysed by immuno¯uorescence, immunohistochemistry, and Western blot analysis. The Elk-1 unlike DElk-1 transfectants showed a shortened and¯attened morphology compared to the parental cells. We have found that calcium ionophore treatment of Rat-1 Elk-1, MCF-7 Elk-1, Rat-1 DElk-1 and MCF-7 DElk-1 transfectants resulted in programmed cell death. These results indicate that constitutive expression of Elk-1 and DElk-1 proteins triggers apoptosis in Rat-1 ®broblasts and breast cancer cells when treated with calcium ionophore.Keywords: Elk-1; DElk-1; apoptosis; calcium ionophore; breast cancer; MCF-7; Rat-1The Elk-1 gene belongs to the ets family of ternary complex factors (TCFs), i.e. Elk-1, SAP1, and NET/ ERP/SAP2/Elk-3 (Rao et al., 1989;Hipskind et al., 1991;Giovane et al., 1994;Lopez et al., 1994;Dalton and Treisman, 1992;Price et al., 1995;Nozaki et al., 1996). The Elk-1 gene codes for at least two alternately spliced products Elk-1 (Rao et al., 1989) and DElk-1 (Rao and Reddy, 1993) which function as transcriptional activators (Rao and Reddy, 1992;Bhattacharya et al., 1993), are substrates for MAP kinases Marias et al., 1993;Hill et al., 1993) and JNK protein kinases (Gupta et al., 1996;Whitmarsh et al., 1995). As mentioned earlier, the Elk-1 protein is a TCF which in association with serum response factor (SRF) forms a ternary complex on the serum response element (SRE) of the c-fos promoter and regulates cfos transcription (Hipskind et al., 1991). The TCF's which includes Elk-1 have three domains with similar sequences and functions. The ets domain mediates DNA binding, the SRF interaction domain interacts with SRF to form a ternary complex with the c-fos SRE and the C-terminal domain activates transcription upon phosphorylation by MAP kinases (Rao et al., 1989;Rao and Reddy, 1992;Dalton and Treisman, 1992;Janknecht et al., 1993Janknecht et al., , 1994Marias et al., 1993;Giovane et al., 1994;Hipskind et al., 1994;Kortenjann et al., 1994;Lopez et al., 1994;Hill et al., 1995;Price et al., 1995;Whitmarsh et al., 1995) and JNK kinases (Gupta et al., 1996). Thus Elk-1 represents a key link between signal transduction and induction of gene transcription.The Gag-Myb-Ets fusion protein, identi®ed in the avian acute leukemia virus E26 was shown to inhibit apoptosis and induce erythroid di erentiation in hematopoietic cells (Athanasiou et al., 1996). Similarly the Ets-1 proto-oncogene was shown to be required for the normal survival and activation of B and T cells while an Ets-1 splice variant was shown to induce apoptosis in human colon cancer cells indicating a role in apoptosis (Bories et al....

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“…To investigate the e ect of Pim-1 expression on c-Mycmediated apoptosis, we used the experimental system described by Evan et al (1992), in which the overexpression of c-Myc causes apoptosis of serumdeprived Rat-1 ®broblasts. We ®rst established Rat-1 clones that stably express c-Myc (Rat-1/c-Myc) by transfecting Rat-1 cells with a plasmid vector (pCEP4cmyc) carrying human c-myc cDNA connected with the cytomegalovirus (CMV) promoter.…”

Section: Resultsmentioning

confidence: 99%

“…However, it has been also demonstrated that the deregulated expression of c-Myc accelerates or induces apoptotic cell death in cells deprived of growth factors (Askew et al, 1991;Evan et al, 1992). Thus, c-myc is not only a positive regulator of cell proliferation and transformation but also a positive regulator of apoptotic cell death.…”

Section: Introductionmentioning

confidence: 99%

Pim-1 kinase stimulates c-Myc-mediated death signaling upstream of caspase-3 (CPP32)-like protease activation

Mochizuki¹,

Kitanaka²,

Noguchi³

et al. 1997

Oncogene

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Pim-1 oncoprotein is a serine/threonine kinase that can closely cooperate with c-Myc in lymphomagenesis, as does Bcl-2. Although the molecular mechanism of this cooperative transformation remains unknown, it is speculated that, similar to Bcl-2, Pim-1 contributes to transformation by inhibiting apoptosis. In this study, therefore, we examined the e ect of Pim-1 expression on c-Myc-mediated apoptosis of Rat-1 ®broblasts triggered by serum deprivation. Our results showed that, rather than inhibiting apoptosis, Pim-1 expression stimulated cMyc-mediated apoptosis in Rat-1 ®broblasts. Pim-1 stimulated c-Myc-mediated apoptosis through an enhancement of the c-Myc-mediated activation of caspase-3 (CPP32)-like proteases, since the suppression of this activity by a speci®c caspase inhibitor abolished the apoptosis stimulation by Pim-1. A kinase-defective Pim-1 mutant failed to stimulate c-Myc-mediated apoptosis, and Pim-1 expression alone in the absence of c-Myc overexpression did not induce apoptosis of serumdeprived Rat-1 cells, indicating that the kinase activity of Pim-1 and the activated c-Myc signaling pathway were required for apoptosis stimulation by Pim-1. Together, these results suggest that Pim-1 oncoprotein stimulates as a serine/threonine kinase the death signaling elicited by c-Myc at a step upstream of caspase-3-like protease activation in Rat-1 ®broblasts. Our results also suggest that Pim-1 kinase might function cooperatively with c-Myc through the phosphorylation of a factor(s) which regulates the common signaling pathway involved in c-Myc-mediated apoptosis and transformation.

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Induction of apoptosis in fibroblasts by c-myc protein

Cited by 2,811 publications

References 31 publications

MIF loss impairs Myc-induced lymphomagenesis

MIF loss impairs Myc-induced lymphomagenesis

Induction of apoptosis by Elk-1 and ΔElk-1 proteins

Pim-1 kinase stimulates c-Myc-mediated death signaling upstream of caspase-3 (CPP32)-like protease activation

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