Identification of a novel Bax–Cdk1 signalling complex that links activation of the mitotic checkpoint to apoptosis

Darweesh, Omeed; Alshehri, Eman; Falquez, Hugo; Lauterwasser, Joachim; Edlich, Frank; Patel, Rajnikant

doi:10.1242/jcs.244152

Cited by 5 publications

(4 citation statements)

References 57 publications

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“…As a result of the present study, we constructed a 6-gene pyroptosis-related signature, including BAK1, CASP5, CASP6, GPX4, GZMA, and CHMP4C. Notably, six genes involved in this signature have been implicated in apoptotic pathways as well (Li et al, 2015;Skotte et al, 2017;Wu et al, 2019;Zhou et al, 2020;Darweesh et al, 2021;Ding et al, 2021). Following apoptotic signals, caspase 8 and caspase 3 initiate pyroptosis by processing GSDMC and GSDME, respectively (Liu et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

A Novel Pyroptosis-Related Signature for Predicting Prognosis and Indicating Immune Microenvironment Features in Osteosarcoma

Zhang

Liu

et al. 2021

Front. Genet.

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Osteosarcoma is a common malignant bone tumor with a propensity for drug resistance, recurrence, and metastasis. A growing number of studies have elucidated the dual role of pyroptosis in the development of cancer, which is a gasdermin-regulated novel inflammatory programmed cell death. However, the interaction between pyroptosis and the overall survival (OS) of osteosarcoma patients is poorly understood. This study aimed to construct a prognostic model based on pyroptosis-related genes to provide new insights into the prognosis of osteosarcoma patients. We identified 46 differentially expressed pyroptosis-associated genes between osteosarcoma tissues and normal control tissues. A total of six risk genes affecting the prognosis of osteosarcoma patients were screened to form a pyroptosis-related signature by univariate and LASSO regression analysis and verified using GSE21257 as a validation cohort. Combined with other clinical characteristics, including age, gender, and metastatic status, we found that the pyroptosis-related signature score, which we named “PRS-score,” was an independent prognostic factor for patients with osteosarcoma and that a low PRS-score indicated better OS and a lower risk of metastasis. The result of ssGSEA and ESTIMATE algorithms showed that a lower PRS-score indicated higher immune scores, higher levels of tumor infiltration by immune cells, more active immune function, and lower tumor purity. In summary, we developed and validated a pyroptosis-related signature for predicting the prognosis of osteosarcoma, which may contribute to early diagnosis and immunotherapy of osteosarcoma.

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Section: Discussionmentioning

confidence: 99%

A Novel Pyroptosis-Related Signature for Predicting Prognosis and Indicating Immune Microenvironment Features in Osteosarcoma

Zhang

Liu

et al. 2021

Front. Genet.

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“…Apart from these CDK1 substrates, BCL2 apoptosis regulator (BCL2), BCL2 apoptosis regulator like 1 (BCL2L1), and dynamin 1 Like (DRP1) are phosphorylated by CDK1, mediating mitochondrial fusion and apoptosis in human cancer cells [114][115][116][117][118][119][120][121] . F-box protein 28 (FBXO28) and carboxypeptidase D (CPD) are phosphorylated by CDK1 increasing ubiquitylation promoting tumorigenesis.…”

Section: Cdk1 Tumor Promotor Substratesmentioning

confidence: 99%

Targeting CDK1 in cancer: mechanisms and implications

2023

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Cyclin dependent kinases (CDKs) are serine/threonine kinases that are proposed as promising candidate targets for cancer treatment. These proteins complexed with cyclins play a critical role in cell cycle progression. Most CDKs demonstrate substantially higher expression in cancer tissues compared with normal tissues and, according to the TCGA database, correlate with survival rate in multiple cancer types. Deregulation of CDK1 has been shown to be closely associated with tumorigenesis. CDK1 activation plays a critical role in a wide range of cancer types; and CDK1 phosphorylation of its many substrates greatly influences their function in tumorigenesis. Enrichment of CDK1 interacting proteins with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted to demonstrate that the associated proteins participate in multiple oncogenic pathways. This abundance of evidence clearly supports CDK1 as a promising target for cancer therapy. A number of small molecules targeting CDK1 or multiple CDKs have been developed and evaluated in preclinical studies. Notably, some of these small molecules have also been subjected to human clinical trials. This review evaluates the mechanisms and implications of targeting CDK1 in tumorigenesis and cancer therapy.

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“…Activation of BAX and BAK1 are actually thought to be the last BCL2 family members involved in the events promoting apoptosis execution in mitosis. However, recently it has been suggested that they are not simply effectors waiting for upstream signals to be integrated, but that they play an active role in mitotic cell death by facilitating CDK1 mediated phosphorylation of pro-survival proteins (34). BAX, and to a lesser degree BAK1, appear to be able to interact with CDK1, targeting it to the outer mitochondrial membrane, where it can phosphorylate BCL2 and BCLX to facilitate apoptosis (34).…”

Section: Mitotic Arrest and Apoptosismentioning

confidence: 99%

Cell Death as a Barrier against CIN and Aneuploidy

Villunger¹,

Weiß²,

Gallob³

et al. 2022

Preprint

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Aneuploidy describes the gain or loss of entire chromosomes or chromosome arms. Already more than 100 years ago, aneuploidy was described to be featured in cancer and it is known today to be present in 68-90 % of cancers, depending on tumour entity. Aneuploidy is implicated to affect cancer growth, therapy response and frequently affects prognosis. Chromosomal instability (CIN) is recognized as the main cause of aneuploidy and is characterised as the fluent process of gaining or losing chromosomes. Chromosomally instable cells need to be kept in check, or cleared, to prohibit the sampling of aneuploid karyotypes able to drive tumorigenesis. Of note, even aneuploid cancer cells often show CIN, a feature that promotes therapy related drug-resistance. Here, we review how CIN can be prevented or limited to spread by the induction of cell death and the relevance of different p53 responses triggered in response to mitotic perturbations to prohibit the formation of cancer driving aneuploidies.

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Identification of a novel Bax–Cdk1 signalling complex that links activation of the mitotic checkpoint to apoptosis

Cited by 5 publications

References 57 publications

A Novel Pyroptosis-Related Signature for Predicting Prognosis and Indicating Immune Microenvironment Features in Osteosarcoma

A Novel Pyroptosis-Related Signature for Predicting Prognosis and Indicating Immune Microenvironment Features in Osteosarcoma

Targeting CDK1 in cancer: mechanisms and implications

Cell Death as a Barrier against CIN and Aneuploidy

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