Ich-1, an Ice/ced-3-related gene, encodes both positive and negative regulators of programmed cell death

Wang, Lin; Miura, Masayuki; Bergeron, Louise; Zhu, Hong; Yuan, Junying

doi:10.1016/s0092-8674(94)90422-7

Cited by 799 publications

(633 citation statements)

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“…Caspase-1 (ICE)-like and caspase-3 (CPP32/Yama)-like proteases are implicated in apoptosis, because their tetrapeptide competitive inhibitors prevent apoptosis induced by a variety of stimuli (reviewed by Martin and Green, 1995). Studies of ice-de®cient mice have shown that ICE (caspase-1) itself is directly involved in Fasmediated apoptosis of thymocytes (Kuida et al, 1995), and the use of Ich-1 s , an isoform of Ich-1, revealed the involvement of Ich-1 L (caspase-2) in at least one form of apoptosis (Wang et al, 1994). Accumulation of neuronal cells in CPP32-de®cient mice also indicates the involvement of CPP32/Yama (caspase-3) in apoptosis in nervous system (Kuida et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…Caspases are translated in their precursor forms and activated by proteolytic cleavage. Some caspases including caspase-1 are likely activated autonomously when overexpressed (Miura et al, 1993;Wang et al, 1994;Kamada et al, 1997), but others such as caspase-3 are not activated without apoptotic stimuli (Hasegawa et al, 1996). Caspases have been suggested to constitute a protease cascade, based on observations that their active forms directly cleave the precursors of other family members in vitro to activate them (reviewed by Martin and Green, 1995).…”

Section: Introductionmentioning

confidence: 99%

“…Bcl-2 localizes in multiple membrane compartments, including the nuclear envelope, endoplasmic reticulum and mitochondrial membranes (Hockenbery et al, 1990;Monaghan et al, 1992;Jacobson et al, 1993;Krajewski et al, 1993;Akao et al, 1994), raising the possibility that Bcl-2 also acts downstream of caspases. Indeed an anti-cell death role for Bcl-2 exerted downstream of active ICE family proteases has been suggested by the observations that (1) using in vitro apoptosis system, apoptotic DNA ladder formation is prevented by a Bcl-2-containing cell lysate, even after an e ector(s) downstream of caspases is activated, as judged by the failure of caspase inhibitors to prevent apoptotic changes in naked nuclei (Enari et al, 1995) and (2) apoptosis induced by transfection with caspase genes which encode precursor forms of proteases is prevented by overexpressed Bcl-2 (Miura et al, 1993;Wang et al, 1994). Using microinjection procedures, we show here that Bcl-2 and Bcl-x L exert their anti-cell death activity only upstream and/or within but not downstream of the caspase cascade.…”

Section: Introductionmentioning

confidence: 99%

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Evidence against a functional site for Bcl-2 downstream of caspase cascade in preventing apoptosis

et al. 1997

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Apoptotic cell death is driven by ICE family proteases (caspases) and negatively regulated by Bcl-2 family proteins. Although it has been shown that Bcl-2 exerts anti-apoptotic activity by blocking a step(s) leading to the activation of caspases, a role for Bcl-2 and Bcl-x L downstream of the caspase cascade has remained unclear. Here, we show that puri®ed active caspase-3 (CPP32/Yama/apopain) and caspase-1 (ICE) induces apoptosis when microinjected into the cytoplasm of cells, con®rming our recent observations, and that the apoptosis is not at all prevented by Bcl-2 and Bcl-x L , which are overexpressed more than su ciently to prevent Fas-mediated and overexpressed procaspase-1-mediated apoptosis. Thus, Bcl-2 and Bcl-x L do not act downstream of the caspase cascade.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evidence against a functional site for Bcl-2 downstream of caspase cascade in preventing apoptosis

et al. 1997

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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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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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Role of caspases 1 and 3 and Bcl-2-related molecules in endothelial cell apoptosis associated with thrombotic microangiopathies

et al. 1998

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We have defined an in vitro model for the study of microvascular endothelial cell (EC) apoptosis mediated by plasma from patients with various forms of thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS). This system reproduces a variety of histopathologic and ultrastructural features of tissue EC involved in TTP/ sporadic HUS, suggesting that apoptotic EC injury is a primary pathophysiologic event in the thrombotic microangiopathies. We now document the ability of tetrapeptide-based inhibitors of interleukin 1␤-converting enzyme (ICE)-like caspase 1 and cysteine protease protein (CPP)-32-like caspase 3, two members of a novel class of cysteine proteases involved in final pathways to apoptosis, to block TTP/sporadic HUS plasma-mediated apoptosis. Overexpression of Bcl-X L via gene transfer suppressed this apoptosis by 70%. Transduction of EC with the Bcl-2 homolog A1 had a more limited protective effect. These findings support a role for apoptosis-linked cysteine proteases in the pathophysiology of TTP and sporadic HUS, and raise the possibility that specific apoptosis inhibitors may have a role in the experimental therapeutics of these syndromes. Am.

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Ich-1, an Ice/ced-3-related gene, encodes both positive and negative regulators of programmed cell death

Cited by 799 publications

References 16 publications

Evidence against a functional site for Bcl-2 downstream of caspase cascade in preventing apoptosis

Evidence against a functional site for Bcl-2 downstream of caspase cascade in preventing apoptosis

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

Role of caspases 1 and 3 and Bcl-2-related molecules in endothelial cell apoptosis associated with thrombotic microangiopathies

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