Doom, a product of the Drosophila mod(mdg4) gene, induces apoptosis and binds to baculovirus inhibitor-of-apoptosis proteins.

A family of baculovirus inhibitor-of-apoptosis (IAP) genes is present in mammals, insects, and baculoviruses, but the mechanism by which they block apoptosis is unknown. We have identified a protein encoded by the Drosophila mod(mdg4) gene which bound to the baculovirus IAPs. This protein induced rapid apoptosis in insect cells, and consequently we have named it Doom. Baculovirus IAPs and P35, an inhibitor of aspartate-specific cysteine proteases, blocked Doom-induced apoptosis. The carboxyl terminus encoded by the 3' exon of the doom cDNA, which distinguishes it from other mod(mdg4) cDNAs, was responsible for induction of apoptosis and engagement of the IAPs. Doom localized to the nucleus, while the IAPs localized to the cytoplasm, but when expressed together, Doom and the IAPs both localized in the nucleus. Thus, IAPs might block apoptosis by interacting with and modifying the behavior of Doom-like proteins that reside in cellular apoptotic pathways.

Download Full-text

Cytosolic expression of dimerization defective mutants of mature Smac potentiate induction of apoptosis without interacting with inhibitor of apoptosis proteins (IAPs)

The FASEB Journal ◽

10.1096/fasebj.23.1_supplement.526.23 ◽

2009 ◽

Vol 23 (S1) ◽

Author(s):

Stephen P. Burke ◽

Jeffrey B. Smith

Keyword(s):

Inhibitor Of Apoptosis ◽

Inhibitor Of Apoptosis Proteins ◽

Induction Of Apoptosis ◽

Apoptosis Proteins

Download Full-text

Sulforaphane Protects Against Ethanol-Induced Apoptosis in Human Neural Crest Cells Through Diminishing Ethanol-Induced Hypermethylation at the Promoters of the Genes Encoding the Inhibitor of Apoptosis Proteins

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.622152 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yihong Li ◽

Huadong Fan ◽

Fuqiang Yuan ◽

Lanhai Lu ◽

Jie Liu ◽

...

Keyword(s):

Neural Crest ◽

Neural Crest Cell ◽

Ethanol Exposure ◽

Inhibitor Of Apoptosis ◽

Inhibitor Of Apoptosis Proteins ◽

Promoter Regions ◽

Genes Encoding ◽

Apoptotic Genes ◽

Induced Apoptosis ◽

Apoptosis Proteins

The neural crest cell (NCC) is a multipotent progenitor cell population that is sensitive to ethanol and is implicated in the Fetal Alcohol Spectrum Disorders (FASD). Studies have shown that sulforaphane (SFN) can prevent ethanol-induced apoptosis in NCCs. This study aims to investigate whether ethanol exposure can induce apoptosis in human NCCs (hNCCs) through epigenetically suppressing the expression of anti-apoptotic genes and whether SFN can restore the expression of anti-apoptotic genes and prevent apoptosis in ethanol-exposed hNCCs. We found that ethanol exposure resulted in a significant increase in the expression of DNMT3a and the activity of DNMTs. SFN treatment diminished the ethanol-induced upregulation of DNMT3a and dramatically reduced the activity of DNMTs in ethanol-exposed hNCCs. We also found that ethanol exposure induced hypermethylation at the promoter regions of two inhibitor of apoptosis proteins (IAP), NAIP and XIAP, in hNCCs, which were prevented by co-treatment with SFN. SFN treatment also significantly diminished ethanol-induced downregulation of NAIP and XIAP in hNCCs. The knockdown of DNMT3a significantly enhanced the effects of SFN on preventing the ethanol-induced repression of NAIP and XIAP and apoptosis in hNCCs. These results demonstrate that SFN can prevent ethanol-induced apoptosis in hNCCs by preventing ethanol-induced hypermethylation at the promoter regions of the genes encoding the IAP proteins and diminishing ethanol-induced repression of NAIP and XIAP through modulating DNMT3a expression and DNMT activity.

Download Full-text

Fludarabine-Induced Apoptosis in Chronic Lymphocytic Leukemia Cells Is Not Affected by Inhibitor of Apoptosis Proteins (IAPS).

Blood ◽

10.1182/blood.v104.11.4833.4833 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4833-4833

Author(s):

Karina Lani Silva ◽

Eric Delfraro de Paula Castro ◽

Deborah Vidal Vasconcellos ◽

Jolie Kiemlian Kwee ◽

Arthur Coelho Moellman ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Lymphocytic Leukemia ◽

Inhibitor Of Apoptosis ◽

Inhibitor Of Apoptosis Proteins ◽

Apoptosis Resistance ◽

Independent Manner ◽

Xiap Expression ◽

Induced Apoptosis ◽

Apoptosis Proteins

Abstract B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of mature lymphocytes due to defective apoptosis. Inhibition of apoptosis also contributes to chemoresistance, mainly in patients in advanced clinical stages. Fludarabine is a potent chemotherapeutic drug used for patients with B-CLL. Despite good initial clinical responses, some patients acquire resistance to this drug. One of the mechanisms through which malignant cells are believed to acquire resistance to apoptosis is by overexpression of inhibitor of apoptosis proteins (IAPs). IAPs are a family of proteins able to block apoptosis either by binding and inhibiting caspases or through caspases-independent mechanisms. To date, overexpression of IAPs has been detected in many types of malignant diseases, including B-CLL. As fludarabine can induce apoptosis trough caspases activation and this proteases could be inhibited by IAPs, we evaluated in this current study, the expression of three members of IAP family (c-IAP1, c-IAP2 and XIAP) by immunocitochemistry in 30 peripheral blood B-CLL specimens and correlated it to fludarabine-induced apoptosis. In parallel, we also evaluated the expression of these IAPs before and after in vitro fludarabine treatment. B-CLL cells were incubated with fludarabine25 m M for 12 hours and the induction of apoptosis were measured by annexin-V assay. The apoptosis index by fludarabine was extremely significant (p < 0.001). Different levels of c-IAP1, c-IAP2 and XIAP expression were commonly found in circulating B-CLL cells. High levels of c-IAP1, c-IAP2 and XIAP expression were observed in 20%, 60,7% and 60% of samples, respectively. However, the overexpression of these IAPs was not correlated with an in vitro fludarabine apoptosis-resistance. Besides, fludarabine was not able to change the levels of IAPs expression as described for other drugs in literature. These results suggest that fludarabine might cause apoptosis by a caspase-independent manner.

Download Full-text