BaxΔ2 Promotes Apoptosis through Caspase-8 Activation in Microsatellite-Unstable Colon Cancer

Zhang, Honghong; Lin, Yu-Ting; Mañas, Adriana; Zhao, Yu; Denning, Mitchell F.; Ma, Li; Xiang, Jialing

doi:10.1158/1541-7786.mcr-14-0162

Cited by 20 publications

(39 citation statements)

References 47 publications

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“…BaxΔ2 exon 6 is essential for aggregation-mediated toxicity and we previously showed that BaxΔ2-induced cell death is through activation of caspase 8 (53). Next, we wanted to know which elements of the C-terminus were critical for the activation of caspase 8.…”

Section: Resultsmentioning

confidence: 99%

“…The Bax negative colon cancer HCT116 subline cell line was generated as described previously (53). All cells were cultured in Dulbecco’s Modification of Eagle’s Medium supplemented with 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

“…BaxΔ2 and its subfamily members are a group of unique functional Bax isoforms initially identified in patients with a family history of mismatch repair deficiency (13, 51–53). BaxΔ2 has a guanine deletion in exon 3 (G8 → G7), which causes a frameshift and pre-mature termination of translation.…”

Section: Introductionmentioning

confidence: 99%

“…However, an alternative splicing event removes most of exon 2 and restores the reading frame, resulting in a full-length functional isoform (BaxΔ2) with 10 new amino acids between the alternative splicing site and the point of the deletion. The rest of the BaxΔ2 sequence is the same as Baxα (13, 51, 53). …”

Section: Introductionmentioning

confidence: 99%

“…However, BaxΔ2 is unable to target mitochondria due to the lack of helix α1 (13, 22, 37–39). Instead, BaxΔ2 forms cytosolic aggregates, promoting apoptosis by activating caspase 8 (13, 51, 53). However, the functional domain(s) for the aggregation and activation of caspase 8 were unknown.…”

Section: Introductionmentioning

confidence: 99%

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The functional domains for Bax∆2 aggregate-mediated caspase 8-dependent cell death

Mañas

Wang

Nelson

et al. 2017

Experimental Cell Research

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BaxΔ2 is a functional pro-apoptotic Bax isoform having alterations in its N-terminus, but sharing the rest of its sequence with Baxα. BaxΔ2 is unable to target mitochondria due to the loss of helix α1. Instead, it forms cytosolic aggregates and activates caspase 8. However, the functional domain(s) responsible for BaxΔ2 behavior have remained elusive. Here we show that disruption of helix α1 makes Baxα mimic the behavior of BaxΔ2. However, the other alterations in the BaxΔ2 N-terminus have no significant impact on aggregation or cell death. We found that the hallmark BH3 domain is necessary but not sufficient for aggregation-mediated cell death. We also noted that the core region shared by Baxα and BaxΔ2 is required for the formation of large aggregates, which is essential for BaxΔ2 cytotoxicity. However, aggregation by itself is unable to trigger cell death without the C-terminus. Interestingly, the C-terminal helical conformation, not its primary sequence, appears to be critical for caspase 8 recruitment and activation. As BaxΔ2 shares core and C-terminal sequences with most Bax isoforms, our results not only reveal a structural basis for BaxΔ2-induced cell death, but also imply an intrinsic potential for aggregate-mediated caspase 8-dependent cell death in other Bax family members.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The functional domains for Bax∆2 aggregate-mediated caspase 8-dependent cell death

Mañas

Wang

Nelson

et al. 2017

Experimental Cell Research

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Microsatellite instability: an update

2015

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Deficient DNA mismatch repair (MMR) results in a strong mutator phenotype known as microsatellite instability (MSI), which is a hallmark of Lynch syndrome-associated cancers. MSI is characterized by length alterations within simple repeated sequences that are called microsatellites. Lynch syndrome is primarily caused by mutations in the MMR genes, mainly MLH1 and MSH2, and less frequently in MSH6, and rarely PMS2, and large genomic rearrangements account for 5-20 % of all mutations. Germ line hemiallelic methylations of MLH1 or MSH2 are termed as epimutations and have been identified as causative of Lynch syndrome. Moreover, germ line 3' deletions of EPCAM gene is involved in MSH2 methylation. MSI is also observed in about 15 % of sporadic colorectal cancer (CRC), gastric cancer (GC), and endometrial cancer (EC), and at lower frequencies in other cancers, often in association with hypermethylation of the MLH1 gene. Trimethylation of histone H3 on Lys36 (H3K36 me3) is an epigenetic histone mark that was required for DNA MMR in vivo. Thus, mutations in the H3K36 trimethyltransferase SETD2 have been reported as a potential cause of MSI. Genetic, epigenetic, and transcriptomic differences have been identified between cancers with and without MSI. Recent comprehensive molecular characterizations of CRC, EC, and GC by The Cancer Genome Atlas indicate that MSI+ cancers are distinct biological entities. The BRAF V600E mutation is specifically associated with sporadic MSI+ CRCs with methylated MLH1, but is not associated with Lynch syndrome-related CRCs. Accumulating evidence indicates a role of interactions between MSI and microRNA (miRNA) in the pathogenesis of MSI-positive (MSI+) cancer. As another new mechanism underlying MSI, overexpression of miR-155 or miR-21 has been shown to downregulate the expression of the MMR genes. Gene targets of frameshift mutations caused by MSI are involved in various cellular functions, including DNA repair (MSH3 and MSH6), cell signaling (TGFBR2 and ACVR2A), apoptosis (BAX), epigenetic regulation (HDAC2 and ARID1A), and miRNA processing (TARBP2 and XPO5), and a subset of MSI+ CRCs reportedly shows the mutated miRNA machinery phenotype. Moreover, microsatellite repeats in miRNA genes, such as hsa-miR-1273c, may be novel MSI targets for CRC, and mutations in noncoding regulatory regions of MRE11, BAX (BaxΔ2), and HSP110 (HSP110ΔE9) may affect the efficiency of chemotherapy. Thus, analyses of MSI and its related molecular alterations in cancers are increasingly relevant in clinical settings, and MSI is a useful screening marker for identifying patients with Lynch syndrome and a prognostic factor for chemotherapeutic interventions. In this review, we summarize recent advances in the pathogenesis of MSI and focus on genome-wide analyses that indicate the potential use of MSI and related alterations as biomarkers and novel therapeutic targets.

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Detection of pro-apoptotic Bax∆2 proteins in the human cerebellum

Mañas

Davis

Lamerand

et al. 2018

Histochem Cell Biol

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Bax∆2 is a pro-apoptotic protein originally discovered in colon cancer patients with high microsatellite instability. Unlike most pro-apoptotic Bax family members, Bax∆2 mediates cell death through a non-mitochondrial caspase 8-dependent pathway. In the scope of analyzing the distribution of Bax∆2 expression in human tissues, we examined a panel of human brain samples. Here, we report four cerebellar cases in which the subjects had no neurological disorder or disease documented. We found Bax∆2 positive cells scattered in all areas of the cerebellum, but most strikingly concentrated in Purkinje cell bodies and dendrites. Two out the four subjects tested had strong Bax∆2-positive staining in nearly all Purkinje cells; one was mainly negative; and one had various levels of positive staining within the same sample. Further genetic analysis of the Purkinje cell layer, collected by microdissection from two subjects, showed that the samples contained G7 and G9 Bax microsatellite mutations. Both subjects were young and had no diseases reported at the time of death. As the distribution of Bax∆2 is consistent with that known for Baxα, but in a less ubiquitous manner, these results may imply a potential function of Bax∆2 in Purkinje cells.

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BaxΔ2 Promotes Apoptosis through Caspase-8 Activation in Microsatellite-Unstable Colon Cancer

Cited by 20 publications

References 47 publications

The functional domains for Bax∆2 aggregate-mediated caspase 8-dependent cell death

The functional domains for Bax∆2 aggregate-mediated caspase 8-dependent cell death

Microsatellite instability: an update

Detection of pro-apoptotic Bax∆2 proteins in the human cerebellum

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