scholarly journals Caspase-8 mutations associated with head and neck cancer differentially retain functional properties related to TRAIL-induced apoptosis and cytokine induction

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Zhibin Cui ◽  
Hadas Dabas ◽  
Brandon C. Leonard ◽  
Jamie V. Shiah ◽  
Jennifer R. Grandis ◽  
...  
Keyword(s):  
Head And Neck ◽  
Functional Properties ◽  
Human Head ◽  
Caspase 8 ◽  
Loss Of Function ◽  
Wild Type ◽  
Apoptosis Pathway ◽  
Amino Terminal ◽  
Cytokine Induction ◽  
Induced Apoptosis

AbstractThe cysteine protease, caspase-8, undergoes dimerization, processing, and activation following stimulation of cells with death ligands such as TRAIL, and mediates TRAIL induction of the extrinsic apoptosis pathway. In addition, caspase-8 mediates TRAIL-induced activation of NF-κB and upregulation of immunosuppressive chemokines/cytokines, via a mechanism independent of caspase-8 catalytic activity. The gene encoding procaspase-8 is mutated in 10% of human head and neck squamous cell carcinomas (HNSCCs). Despite a paucity of experimental evidence, HNSCC-associated caspase-8 mutations are commonly assumed to be loss of function. To investigate their functional properties and phenotypic effects, 18 HNSCC-associated caspase-8 mutants were expressed in doxycycline-inducible fashion in cell line models wherein the endogenous wild-type caspase-8 was deleted. We observed that 5/8 mutants in the amino-terminal prodomain, but 0/10 mutants in the carboxyl-terminal catalytic region, retained an ability to mediate TRAIL-induced apoptosis. Caspase-8 proteins with mutations in the prodomain were defective in dimerization, whereas all ten of the catalytic region mutants efficiently dimerized, revealing an inverse relationship between dimerization and apoptosis induction for the mutant proteins. Roughly half (3/8) of the prodomain mutants and 9/10 of the catalytic region mutants retained the ability to mediate TRAIL induction of immunosuppressive CXCL1, IL-6, or IL-8. Doxycycline-induced expression of wild-type caspase-8 or a representative mutant led to an increased percentage of T and NKT cells in syngeneic HNSCC xenograft tumors. These findings demonstrate that HNSCC-associated caspase-8 mutants retain properties that may influence TRAIL-mediated apoptosis and cytokine induction, as well as the composition of the tumor microenvironment.

scholarly journals Host Insect Inhibitor-of-Apoptosis SfIAP Functionally Replaces Baculovirus IAP but Is Differentially Regulated by Its N-Terminal Leader

2010 ◽  
Vol 84 (21) ◽  
pp. 11448-11460 ◽  
Author(s):  
Rebecca J. Cerio ◽  
Rianna Vandergaast ◽  
Paul D. Friesen
Keyword(s):  
Selective Advantage ◽  
Biochemical Properties ◽  
Inhibitor Of Apoptosis ◽  
Loss Of Function ◽  
Wild Type ◽  
Host Insect ◽  
Orgyia Pseudotsugata ◽  
Induced Apoptosis ◽  
Lepidopteran Host ◽  
Maximal Stability

ABSTRACT The inhibitor-of-apoptosis (IAP) proteins encoded by baculoviruses bear a striking resemblance to the cellular IAP homologs of their invertebrate hosts. By virtue of the acquired selective advantage of blocking virus-induced apoptosis, baculoviruses may have captured cellular IAP genes that subsequently evolved for virus-specific objectives. To compare viral and host IAPs, we defined antiapoptotic properties of SfIAP, the principal cellular IAP of the lepidopteran host Spodoptera frugiperda. We report here that SfIAP prevented virus-induced apoptosis as well as viral Op-IAP3 (which is encoded by the Orgyia pseudotsugata nucleopolyhedrovirus) when overexpressed from the baculovirus genome. Like Op-IAP3, SfIAP blocked apoptosis at a step prior to caspase activation. Both of the baculovirus IAP repeats (BIRs) were required for SfIAP function. Moreover, deletion of the C-terminal RING motif generated a loss-of-function SfIAP that interacted and dominantly interfered with wild-type SfIAP. Like Op-IAP3, wild-type SfIAP formed intracellular homodimers, suggesting that oligomerization is a functional requirement for both cellular and viral IAPs. SfIAP possesses a ∼100-residue N-terminal leader domain, which is absent among all viral IAPs. Remarkably, deletion of the leader yielded a fully functional SfIAP with dramatically increased protein stability. Thus, the SfIAP leader contains an instability motif that may confer regulatory options for cellular IAPs that baculovirus IAPs have evolved to bypass for maximal stability and antiapoptotic potency. Our findings that SfIAP and viral IAPs have common motifs, share multiple biochemical properties including oligomerization, and act at the same step to block apoptosis support the hypothesis that baculoviral IAPs were derived by acquisition of host insect IAPs.

Fenretinide-induced apoptosis of human head and neck squamous carcinoma cell lines☆☆☆★★★

1998 ◽  
Vol 118 (4) ◽  
pp. 464-471 ◽  
Author(s):  
RICHARD L. SCHER ◽  
WILFRED SAITO ◽  
RICHARD K. DODGE ◽  
WILLIAM J. RICHTSMEIER ◽  
ROBERT L. FINE
Keyword(s):  
Head And Neck ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Squamous Carcinoma ◽  
Human Head ◽  
Carcinoma Cell Lines ◽  
Squamous Carcinoma Cell ◽  
Induced Apoptosis

scholarly journals SLC25A21 Suppresses Cell Growth in Bladder Cancer Via The Reactive Oxygen Species-Mediated Mitochondrion-Dependent Apoptosis Pathway

2021 ◽  
Author(s):  
Yong Wang ◽  
Jiawen Gao ◽  
Shasha Hu ◽  
Weiting Zeng ◽  
Hongjun Yang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Treatment Strategies ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Apoptosis Pathway ◽  
Normal Tissues ◽  
Induced Apoptosis ◽  
New Diagnosis

Abstract Background: Bladder cancer (BCa) is a commonly diagnosed malignancy worldwide that has poor survival depending on its intrinsic biologic aggressiveness and a peculiar radio- and chemoresistance features. Gaining a better understanding of tumorigenesis and developing new diagnosis and treatment strategies for BCa is important for improving BCa clinical outcome. SLC25 family member 21 (SLC25A21), a carrier transporting C5-C7 oxodicarboxylates, has been reported to contribute to oxoadipate acidemia. However, the potential role of SLC25A21 in cancer remains absolutely unknown. Methods: The expression levels of SLC25A21 in BCa and normal tissues were examined by real-time PCR and immunohistochemistry. Gain-of- and loss-of-function experiments were performed to detect the biological functions of SLC25A21 in vitro and in vivo by CCK-8 assay, plate colony formation assay, cell migration, invasion assay and experimental animal models. The subcellular distribution of substrate mediated by SLC25A21, mitochondrial membrane potential and ROS production were assessed to explore the potential mechanism of SLC25A21 in BCa.Results: We found that the expression of SLC25A21 was downregulated in BCa tissues compared to normal tissues. A significant positive correlation between decreased SLC25A21 expression and poor prognosis was observed in BCa patients. Overexpression of SLC25A21 significantly inhibited cell proliferation, migration and invasion and induced apoptosis in vitro. Moreover, the enhanced SLC25A21 expression significantly suppressed tumor growth in a xenograft mouse model. Furthermore, we revealed that SLC25A21 suppressed BCa growth by inducing the efflux of mitochondrial α-KG to the cytosol, decreasing to against oxidative stress, and activating the ROS-mediated mitochondrion-dependent apoptosis pathway. Conclusions: Our findings provide the first link between SLC25A21 expression and BCa and demonstrate that SLC25A21 acts as a crucial suppressor in BCa progression, which may help to provide new targets for BCa intervention.

scholarly journals Leukemic HRX Fusion Proteins Inhibit GADD34-Induced Apoptosis and Associate with the GADD34 and hSNF5/INI1 Proteins

1999 ◽  
Vol 19 (10) ◽  
pp. 7050-7060 ◽  
Author(s):  
Haskell T. Adler ◽  
Rebecca Chinery ◽  
Daniel Y. Wu ◽  
Steven J. Kussick ◽  
John M. Payne ◽  
...  
Keyword(s):  
Fusion Proteins ◽  
Chromosomal Abnormalities ◽  
Protein A ◽  
Wild Type ◽  
Chromosomal Locus ◽  
Amino Terminal ◽  
Apoptotic Effect ◽  
The Difference ◽  
Induced Apoptosis ◽  
First Time

ABSTRACT One of the most common chromosomal abnormalities in acute leukemia is a reciprocal translocation involving the HRX gene (also called MLL, ALL-1, or HTRX) at chromosomal locus 11q23, resulting in the formation of HRX fusion proteins. Using the yeast two-hybrid system and human cell culture coimmunoprecipitation experiments, we show here that HRX proteins interact directly with the GADD34 protein. We have found that transfected cells overexpressing GADD34 display a significant increase in apoptosis after treatment with ionizing radiation, indicating that GADD34 expression not only correlates with apoptosis but also can enhance apoptosis. The amino-terminal third of the GADD34 protein was necessary for this observed increase in apoptosis. Furthermore, coexpression of three different HRX fusion proteins (HRX-ENL, HRX-AF9, and HRX-ELL) had an anti-apoptotic effect, abrogating GADD34-induced apoptosis. In contrast, expression of wild-type HRX gave rise to an increase in apoptosis. The difference observed here between wild-type HRX and the leukemic HRX fusion proteins suggests that inhibition of GADD34-mediated apoptosis may be important to leukemogenesis. We also show here that GADD34 binds the human SNF5/INI1 protein, a member of the SNF/SWI complex that can remodel chromatin and activate transcription. These studies demonstrate, for the first time, a gain of function for leukemic HRX fusion proteins compared to wild-type protein. We propose that the role of HRX fusion proteins as negative regulators of post-DNA-damage-induced apoptosis is important to leukemia progression.

scholarly journals Nitrosylcobalamin Promotes Cell Death via S Nitrosylation of Apo2L/TRAIL Receptor DR4

2006 ◽  
Vol 26 (15) ◽  
pp. 5588-5594 ◽  
Author(s):  
Zhuo Tang ◽  
Joseph A. Bauer ◽  
Bei Morrison ◽  
Daniel J. Lindner
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Human Cancer ◽  
Death Receptor ◽  
The Other ◽  
Caspase 8 ◽  
Trail Receptor ◽  
Wild Type ◽  
Human Cancer Cell Lines ◽  
Induced Apoptosis

ABSTRACT We have previously demonstrated that nitrosylcobalamin (NO-Cbl), an analogue of vitamin B12 that delivers nitric oxide (NO), had potent antiproliferative activity against several human cancer cell lines. NO-Cbl induced apoptosis via a death receptor/caspase-8 pathway. In this study, we demonstrate that a functional Apo2L/TRAIL receptor was necessary for the induction of cell death by NO-Cbl. Furthermore, the Apo2L/TRAIL death receptor DR4 (TRAIL R1) was S nitrosylated following NO-Cbl treatment. Human melanoma (A375), renal carcinoma (ACHN), and ovarian carcinoma (NIH-OVCAR-3) cells were treated with NO-Cbl and subjected to the biotin switch assay; S-nitrosylated DR4 was detected in all three cell lines. NO-Cbl treatment did not cause S nitrosylation of DR5. The seven cysteine residues located in the cytoplasmic domain of DR4 were individually point mutated to alanines. NIH-OVCAR-3 cells expressing the DR4 C336A mutation lacked S nitrosylation following NO-Cbl treatment. Overexpression of wild-type DR4 sensitized cells to growth inhibition by NO-Cbl. Cells expressing the DR4 C336A mutant were more resistant to NO-Cbl and Apo2L/TRAIL than were the other six C-A mutations or wild-type cells. The C336A mutant also displayed blunted caspase-8 enzymatic activity following NO-Cbl treatment compared to the other mutants. Thus, DR4 residue C336 becomes S nitrosylated and promotes apoptosis following NO-Cbl treatment.

Two Dominant Mutations in the Mouse Fused Gene Are the Result of Transposon Insertions

Genetics ◽  
1997 ◽  
Vol 147 (2) ◽  
pp. 777-786 ◽  
Author(s):  
Thomas J Vasicek ◽  
Li Zeng ◽  
X-J Guan ◽  
Tong Zhang ◽  
Frank Costantini ◽  
...  
Keyword(s):  
Axis Formation ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Loss Of Function ◽  
Wild Type ◽  
Amino Terminal ◽  
Rgs Domain ◽  
Transposon Insertions ◽  
Fused Gene ◽  
Intracisternal A Particle

The mouse Fused locus encodes a protein that has been implicated in the regulation of embryonic axis formation. The protein, which has been named Axin to distinguish it from the product of the unrelated Drosophila melanogaster gene fused, contains regions of similarity to the RGS (regulators of G-protein signaling) family of proteins as well as to dishevelled, a protein that acts downstream of Wingless in D. melanogaster. Loss-of-function mutations at Fused lead to lethality between days 8 and 10 of gestation. Three dominant mutations result in a kinked tail in heterozygotes. Two of the dominant mutations, Fused and Knobbly, result from insertions of intracisternal A particle retrotransposons into the gene. The insertion in Fused, within the sixth intron, creates a gene that produces wild-type transcripts as well as mutant transcripts that initiate at both the authentic promoter and the 3′-most long terminal repeat of the insertion. Knobbly, an insertion of the retrotransposon into exon 7, precludes the production of wild-type protein. Thus the Fused homozygote is viable whereas Knobbly is a recessive embryonic lethal. In both mutants the dominant kink-tailed phenotype is likely to result from the synthesis of similar amino-terminal fragments of Axin protein that would contain the RGS domain, but lack the dishevelled domain.

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