Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis

Rathmell, Jeffrey C.; Lindsten, Tullia; Zong, Wei‐Xing; Cinalli, Ryan M.; Thompson, Craig B.

doi:10.1038/ni834

Cited by 274 publications

(289 citation statements)

References 43 publications

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“…21 Although they seem to be redundant in some circumstances, 22,23 there is a clear preference for one over the other in some situations. 24 The activation of Bax/Bak is the consequence of the activation of members of the BH3-only group of Bcl-2 protein family members.…”

Section: Mva-de3l Activates the Mitochondrial Pathway And Utilises Noxamentioning

confidence: 99%

Modified vaccinia virus Ankara protein F1L is a novel BH3-domain-binding protein and acts together with the early viral protein E3L to block virus-associated apoptosis

Fischer¹,

Ludwig

Holzapfel³

et al. 2005

Cell Death Differ

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Infection with viruses often protects the infected cell against external stimuli to apoptosis. Here we explore the balance of apoptosis induction and inhibition for infection with the modified vaccinia virus Ankara (MVA), using two MVA mutants with experimentally introduced deletions. Deletion of the E3L-gene from MVA transformed the virus from an inhibitor to an inducer of apoptosis. Noxa-deficient mouse embryonic fibroblasts (MEF) were resistant to MVA-DE3L-induced apoptosis. When the gene encoding F1L was deleted from MVA, apoptosis resulted that required Bak or Bax. MVA-DF1L-induced apoptosis was blocked by Bcl-2. When expressed in HeLa cells, F1L blocked apoptosis induced by forced expression of the BH3-only proteins, Bim, Puma and Noxa. Finally, biosensor analysis confirmed direct binding of F1L to BH3 domains. These data describe a molecular framework of how a cell responds to MVA infection by undergoing apoptosis, and how the virus blocks apoptosis by interfering with critical steps of its signal transduction.

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Section: Mva-de3l Activates the Mitochondrial Pathway And Utilises Noxamentioning

confidence: 99%

Modified vaccinia virus Ankara protein F1L is a novel BH3-domain-binding protein and acts together with the early viral protein E3L to block virus-associated apoptosis

Fischer¹,

Ludwig

Holzapfel³

et al. 2005

Cell Death Differ

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“…Consistent with the notion that BAX and BAK have essential overlapping functions in the BCL-2-regulated apoptotic pathway, cells from Bax −/− Bak −/− mice are markedly resistant to diverse anticancer agents. [138][139][140] Notably, different anticancer agents require different BH3-only proteins for cell killing. PUMA is critical for therapeutic responses to γ-irradiation as well as to DNA-damaging drugs, with contributions from NOXA and also BIM (which does not appear to be a direct transcriptional target of p53) in at least certain non-transformed and malignant cell types.…”

Section: The Role Of the Bcl-2-regulated Apoptotic Pathway In Cancer mentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

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Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

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“…50,51 This dramatic resistance appears to be more dramatic than the resistance observed in mice deficient in BIM demonstrating the critical role of BAX and BAK in integrating apoptotic signaling.…”

Section: Cytokines Regulate Survival In Early Lymphocyte Developmentmentioning

confidence: 99%

Apoptosis in the development of the immune system

Opferman

2007

Cell Death Differ

118

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Apoptosis is a conserved genetic program critical for the development and homeostasis of the immune system. During the early stages of lymphopoiesis, growth factor signaling is an essential regulator of homeostasis by regulating the survival of lymphocyte progenitors. During differentiation, apoptosis ensures that lymphocytes express functional antigen receptors and is essential for eliminating lymphocytes with dangerous self-reactive specificities. Many of these critical cell death checkpoints during immune development are regulated by the BCL-2 family of proteins, which is comprised of both pro-and antiapoptotic members, and members of the tumor necrosis factor death receptor family. Aberrations in the expression or function of these cell death modulators can result in pathological conditions including immune deficiency, autoimmunity, and cancer. This review will describe how apoptosis regulates these critical control points during immune development.

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Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis

Cited by 274 publications

References 43 publications

Modified vaccinia virus Ankara protein F1L is a novel BH3-domain-binding protein and acts together with the early viral protein E3L to block virus-associated apoptosis

Modified vaccinia virus Ankara protein F1L is a novel BH3-domain-binding protein and acts together with the early viral protein E3L to block virus-associated apoptosis

The BCL-2 protein family, BH3-mimetics and cancer therapy

Apoptosis in the development of the immune system

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