Lessons from gain‐ and loss‐of‐function models of pro‐survival Bcl2 family proteins: implications for targeted therapy

Sochalska, Maja; Tuzlak, Selma; Egle, Alexander

doi:10.1111/febs.13188

Cited by 55 publications

(51 citation statements)

References 122 publications

(199 reference statements)

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“…Additional cell cycle regulator CDKN1B was significantly downregulated in PDTCs (Table 2). Finally, we demonstrate that the apoptosis related gene BCL2, previously reported to be associated with a number of malignancies by other groups [16, 17], exhibits a downregulation in FTC, PTC and PDTC, with a progressive increase in fold change associated with malignancy progression (Table 5, [8]).…”

Section: Discussionsupporting

confidence: 62%

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Identification of CHEK1, SLC26A4, c-KIT, TPO and TG as new biomarkers for human follicular thyroid carcinoma

et al. 2016

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The search for preoperative biomarkers for thyroid malignancies, in particular for follicular thyroid carcinoma (FTC) diagnostics, is of utmost clinical importance. We thus aimed at screening for potential biomarker candidates for FTC. To evaluate dynamic alterations in molecular patterns as a function of thyroid malignancy progression, a comparative analysis was conducted in clinically distinct subgroups of FTC and poorly differentiated thyroid carcinoma (PDTC) nodules. NanoString analysis of FFPE samples was performed in 22 follicular adenomas, 56 FTC and 25 PDTC nodules, including oncocytic and non-oncocytic subgroups. The expression levels of CHEK1, c-KIT, SLC26A4, TG and TPO were significantly altered in all types of thyroid carcinomas. Based on collective changes of these biomarkers which correlating among each other, a predictive score has been established, allowing for discrimination between benign and FTC samples with high sensitivity and specificity. Additional transcripts related to thyroid function, cell cycle, circadian clock, and apoptosis regulation were altered in the more aggressive oncocytic subgroups only, with expression levels correlating with disease progression. Distinct molecular patterns were observed for oncocytic and non-oncocytic FTCs and PDTCs. A predictive score correlation coefficient based on collective alterations of identified here biomarkers might help to improve the preoperative diagnosis of FTC nodules.

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Section: Discussionsupporting

confidence: 62%

“…Alterations in CHEK1 levels have been previously described by us in PTC (Table 5, [8]), and in a number of non-thyroid malignancies by other groups [16, 17]. A recent report reveals that CHEK2 (but not CHEK1 ) levels are altered in PDTC and ATC [18].…”

Section: Discussionmentioning

confidence: 60%

Identification of CHEK1, SLC26A4, c-KIT, TPO and TG as new biomarkers for human follicular thyroid carcinoma

et al. 2016

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“…On the other hand, several observations also argue against this model. First, it has been observed that Mcl1 gene deletion is lethal in a variety of cell lineages [104–109], although this might reflect an obligate role for Mcl-1 in oxidative phosphorylation within mitochondria rather than its anti-apoptotic role on the surface mitochondria [106]. Moreover, recent results suggest that the relative potencies of these proteins might reflect their relative expression levels rather than the range of pro-apoptotic proteins neutralized [110].…”

Section: Advances In Understanding Regulation Of Anti-apoptotic Bcmentioning

confidence: 99%

Emerging understanding of Bcl-2 biology: Implications for neoplastic progression and treatment

Correia

Lee

Meng

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

133

117

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Bcl-2, the founding member of a family of apoptotic regulators, was initially identified as the protein product of a gene that is translocated and overexpressed in greater than 85% of follicular lymphomas (FLs). Thirty years later we now understand that Bcl-2 modulates the intrinsic apoptotic pathway by binding and neutralizing the mitochondrial permeabilizers Bax and Bak as well as a variety of pro-apoptotic proteins, including the cellular stress sensors Bim, Bid, Puma, Bad, Bmf and, under some conditions, Noxa. Despite extensive investigation of all of these proteins, important questions remain. For example, how Bax and Bak breach the outer mitochondrial membrane remains poorly understood. Likewise, how the functions of anti-apoptotic Bcl-2 family members such as eponymous Bcl-2 are affected by phosphorylation or cancer-associated mutations has been incompletely defined. Finally, whether Bcl-2 family members can be successfully targeted for therapeutic advantage is only now being investigated in the clinic. Here we review recent advances in understanding Bcl-2 family biology and biochemistry that begin to address these questions.

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“…Deletion of individual anti-apoptotic Bcl-2-proteins in mice produces rather different phenotypes, ranging from male sterility (deletion of Bcl-w) and cell death of specific populations in various organs (loss of Bcl-2) to embryonic lethality (loss of Bcl-X or Mcl-1). 9 …”

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confidence: 99%

Anti-apoptotic Bcl-XL but not Mcl-1 contributes to protection against virus-induced apoptosis

et al. 2016

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Infection of mammalian cells with viruses often induces apoptosis. How the recognition of viruses leads to apoptosis of the infected cell and which host cell factors regulate this cell death is incompletely understood. In this study, we focussed on two major anti-apoptotic proteins of the host cell, whose abundance and activity are important for cell survival, the Bcl-2-like proteins Mcl-1 and Bcl-XL. During infection of epithelial cells and fibroblasts with modified vaccinia virus Ankara (MVA), Mcl-1 protein levels dropped but the MVA Bcl-2-like protein F1L could replace Mcl-1 functionally; a similar activity was found in vaccinia virus (VACV)-infected cells. During infection with murine cytomegalovirus (MCMV), Mcl-1-levels were not reduced but a viral Mcl-1-like activity was also generated. Infection of mouse macrophages with any of these viruses, on the other hand, induced apoptosis. Virus-induced macrophage apoptosis was unaltered in the absence of Mcl-1. However, apoptosis was substantially increased in infected Bcl-XL-deficient macrophages or macrophages treated with the Bcl-2/Bcl-XL-inhibitor ABT-737. Genetic loss of Bcl-XL or treatment of macrophages with ABT-737 reduced the generation of infectious VACV. These data show that Mcl-1 is dispensable for the regulation of apoptosis during infection with different large DNA viruses, either because the viruses replace its function (in fibroblasts and epithelial cells) or because the pro-apoptotic activity generated by the infection appears not to be blocked by it (in macrophages). Bcl-XL, on the other hand, can be important to maintain survival of virus-infected cells, and its activity can determine outcome of the infection.

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Lessons from gain‐ and loss‐of‐function models of pro‐survival Bcl2 family proteins: implications for targeted therapy

Cited by 55 publications

References 122 publications

Identification of CHEK1, SLC26A4, c-KIT, TPO and TG as new biomarkers for human follicular thyroid carcinoma

Identification of CHEK1, SLC26A4, c-KIT, TPO and TG as new biomarkers for human follicular thyroid carcinoma

Emerging understanding of Bcl-2 biology: Implications for neoplastic progression and treatment

Anti-apoptotic Bcl-XL but not Mcl-1 contributes to protection against virus-induced apoptosis

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