Contrasting Effects of IG20 and Its Splice Isoforms, MADD and DENN-SV, on Tumor Necrosis Factor α-induced Apoptosis and Activation of Caspase-8 and -3

Al-Zoubi, Adeeb; Efimova, Elena V.; Kaithamana, Shashi; Martinez, Osvaldo; El-Idrissi, Mohammed El Azami; Dogan, Rukiye E.; Prabhakar, Bellur S.

doi:10.1074/jbc.m104835200

Cited by 57 publications

(99 citation statements)

References 27 publications

(24 reference statements)

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“…However, IG20pa rendered cells highly susceptible to apoptosis induced by different death signals including TRAIL, and suppressed cell proliferation. In contrast, we had found that DENN-SV is overexpressed in tumor tissues and cancer cell lines, and expression of exogenous DENN-SV could confer resistance to apoptosis and enhance cell proliferation (Al-Zoubi et al, 2001;Efimova et al, 2003Efimova et al, , 2004Ramaswamy et al, 2004). These observations indicated that IG20-SVs could differentially regulate cell proliferation and death.…”

Section: Discussionmentioning

confidence: 92%

“…These four IG20-SVs are distinguished by differential splicing of exons 13L and 16. Relative to IG20pa, MADD, IG20-SV2 and DENN-SV lack the expression of exon 16 or 13L or both (Al-Zoubi et al, 2001).…”

Section: Introductionmentioning

confidence: 90%

“…The IG20 (Insulinoma-Glucagonoma) is one such gene that can encode at least four different splice variants (SVs), namely IG20pa (i.e., IG20 proapoptotic), MADD/ DENN, IG20-SV2 and DENN-SV (Goto et al, 1992;Lee, 1996, 1998;Cunningham, 1996;Schievella et al, 1997;Al-Zoubi et al, 2001). These four IG20-SVs are distinguished by differential splicing of exons 13L and 16.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, it plays an important role in neurotransmission (Zhang et al, 1998;Tanaka et al, 2001;Yamaguchi et al, 2002), neurodegeneration (Del Villar and Miller, 2004) and guanine nucleotide exchange (Wada et al, 1997;Brown and Howe, 1998;Iwasaki and Toyonaga, 2000;Levivier et al, 2001). These divergent functions are most likely mediated through alternative splicing (Chow et al, 1998;Al-Zoubi et al, 2001;Efimova et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, contrasting effects of IG20-SVs, noted earlier, can only be clarified by knocking down individual IG20-SVs and determining the consequent effects. This posed several challenges because IG20-SVs differ from each other only by the differential expression of exons 13L (130 bp) and 16 (60 bp) (Al-Zoubi et al, 2001). However, using small hairpin RNAs (shRNAs) that specifically target exons 13L, 15 and 16, we were able to selectively knock down either all or different combinations of IG20-SVs in HeLa and PA-1 cancer cell lines, and determine their role in cell survival.…”

Section: Introductionmentioning

confidence: 99%

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MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival

et al. 2006

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The IG20 gene is overexpressed in human tumors and cancer cell lines, and encodes at least four splice variants (SVs) namely, IG20pa, MADD, IG20-SV2 and DENN-SV. Earlier, gain-of-function studies showed that IG20-SVs can exhibit diverse functions and play a critical role in cell proliferation and apoptosis. Expression of exogenous IG20pa or DENN-SV rendered cells either susceptible or resistant to induced apoptosis, respectively, whereas MADD and IG20-SV2 had no apparent effect. In order to understand the contrasting effects of the IG20-SVs in a physiologically more relevant system, we expressed exonspecific small hairpin RNAs (shRNAs) to selectively knockdown specific IG20-SVs. Consistent with an earlier study, knockdown of all IG20-SVs resulted in spontaneous apoptosis of HeLa and PA-1 cells. In addition, we unambiguously demonstrated that knockdown of MADD can render cells susceptible to spontaneous apoptosis but had no discernible effect on cell proliferation, colony size or cell cycle progression. Moreover, expression of MADD alone, and not DENN-SV, in the absence of endogenous IG20-SVs was sufficient to prevent spontaneous apoptosis. Our results show the utility of shRNAs for selective knockdown of particular IG20-SVs and their potential therapeutic value in cancer. Further, they demonstrate that MADD alone is sufficient and necessary for cancer cell survival.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival

et al. 2006

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Antisense abrogation of DENN expression induces apoptosis of leukemia cells in vitro, causes tumor regression in vivo and alters the transcription of genes involved in apoptosis and the cell cycle

Lim

Yeo

Chow

2003

Intl Journal of Cancer

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We previously reported that messenger RNA expression of DENN (differentially expressed in normal and neoplastic cells) is considerably higher in cancer cell lines than in normal cells. In our present study, we established that certain cancer cell lines express conspicuously higher levels of the 2 DENN isoforms in contrast to the 2 pro-apoptotic IG20 isoforms. Antisense DENN oligodeoxynucleotide treatment of K36 cells in vitro induced extensive apoptosis, while antisense DENN silencing of K36 tumor-bearing mice caused significant tumor regression in vivo. Compared to wild-type murine embryonic fibroblasts, antisense treatment of NFB and TNFR1 KO cells resulted in markedly more pronounced cell death, whereas antisense-treated TNF␣ and TNFR2 knockouts exhibited less prominent apoptosis. Cell viability and apoptosis were authenticated by flow cytometry, membrane integrity, TUNEL, annexin V assays, histology and electron microscopy. Antisense abrogation of DENN expression culminated in upregulated expression of TNFR2, TRAIL and Fas, but downregulation of TNF␣, TNFR1 and cyclin D3. Key words: DENN; MADD; IG20; splice variants; TNF␣; TNF␣ receptors; Fas; antisense; apoptosis; tumor regressionCellular homeostasis requires a delicate balance between cell proliferation and programmed cell death, or apoptosis. The latter constitutes a crucial mechanism that is tightly regulated by a network of molecular circuits governing cell death and survival. Proteins that either induce or inhibit apoptosis participate in signaling pathways that elicit or inhibit the activation of cell death proteases or caspases. The pathogenesis of cancer may involve dysregulated apoptosis, given that such defects are common in malignant cells. 1 Tumor necrosis factor alpha (TNF␣) is a multifunctional cytokine that belongs to a family of ligands with a related family of receptor molecules. Its multifarious activities range from cell proliferative, inflammatory and immune mechanisms, to destructive cellular events, such as apoptosis and necrosis. In order to orchestrate and achieve its cellular roles, TNF␣ triggers numerous signaling pathways and controls downstream molecules, such as transcription factors and G proteins. 2 For example, administration of anti-TNF␣ antibodies to young mice causes severe but transient retardation in growth and body weight. 3 Members of the TNF receptor (TNFR) family include the 2 TNFR isotypes, TNFR1 (55 kD) and TNFR2 (75 kD), which perform distinct roles in various tissues. TNFR proteins are involved in the regulation of cellular homeostatic phenomena including cellular development, differentiation, survival and apoptosis, as well as in pathophysiologic conditions. Death domain receptors represent a subgroup of TNFRs that are defined according to their functional similarities and the common death domain within their cytoplasmic tails. 4 Activated TNFRs associate with distinct adaptor proteins to modulate multiple signaling pathways. The most notable signaling processes involving TNFR family proteins are those culminat...

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MADD Is a Downstream Target of PTEN in Triggering Apoptosis

Jayarama

Ganesh

et al. 2013

J of Cellular Biochemistry

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Mitogen-activated kinase activating death domain containing protein (MADD) is abundantly expressed in cancer cells and necessary for maintaining cancer cell survival. However, this survival function of MADD is dependent upon its phosphorylation by protein kinase B (Akt). The tumour suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a lipid phosphatase that negatively regulates the phosphatidylinositol 3-kinase (PI3K)-Akt signalling pathway. The downstream targets of PTEN in triggering apoptosis have not yet been completely identified. Here, we report that MADD can act as a pro-apoptotic factor to initiate apoptosis when its phosphorylation is attenuated by PTEN. Our data show that tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) induced a reduction in MADD phosphorylation with a concomitant up-regulation of PTEN. Knock down of PTEN using a specific siRNA prevented TRAIL-induced reduction in pMADD levels. Surprisingly, Akt non-phopshorylated MADD translocated from the plasma membrane to cytoplasm where it bound to 14-3-3 and displaced 14-3-3 associated Bax, which translocated to mitochondria resulting in cytochrome-C release. Taken together, our data reveal that PTEN can convey the death signal by preventing MADD phosphorylation by Akt.

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Contrasting Effects of IG20 and Its Splice Isoforms, MADD and DENN-SV, on Tumor Necrosis Factor α-induced Apoptosis and Activation of Caspase-8 and -3

Cited by 57 publications

References 27 publications

MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival

MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival

Antisense abrogation of DENN expression induces apoptosis of leukemia cells in vitro, causes tumor regression in vivo and alters the transcription of genes involved in apoptosis and the cell cycle

MADD Is a Downstream Target of PTEN in Triggering Apoptosis

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