Apoptosis regulator Bcl-w is essential for spermatogenesis but appears otherwise redundant

Print, Cristin G.; Loveland, Kate L; Gibson, Leonie; Meehan, Terry; Stylianou, Anna; Wreford, Nigel G.; Kretser, David M de; Metcalf, Donald; Köntgen, Frank; Adams, Jerry M.; Cory, Suzanne

doi:10.1073/pnas.95.21.12424

Cited by 299 publications

(223 citation statements)

References 43 publications

(51 reference statements)

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“…7,8,13,14 On the other hand, the mice with systemic deletion of the mcl-1 or bcl-x gene died in the embryo stage due to implantation failure or erythrocyte and neuronal apoptosis, respectively, 6,29 which did not provide information about their involvement in the survival of the megakaryocytic lineage. However, Pf4-Cre transgenic mice have recently been developed, and any target gene can be deleted exclusively from their megakaryocytes and platelets.…”

Section: Discussionmentioning

confidence: 99%

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Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages

et al. 2012

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Section: Discussionmentioning

confidence: 99%

“…12 Genetic studies deleting other anti-apoptotic Bcl-2 family genes have not reported any abnormality of the megakaryocytic lineage. 7,8,13,14 Therefore, the essential anti-apoptotic actors regulating survival of the megakaryocytic lineage, especially megakaryocytes, have been unclear and disputed.…”

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confidence: 99%

Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages

et al. 2012

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“…This single finding is consistent with inhibition of cell cycle reentry or G1 to S transition by BCL-w overexpression, but the physiological significance of this was not substantiated in bcl-w À/À mice. 36 MCL-1 was originally identified as an upregulated gene in a human myeloblastic leukemia cell line induced to differentiate in the monocyte lineage. 37 Overexpression of this gene in cell lines caused decreased BrdU uptake and slower doubling rate.…”

Section: Other Antiapoptotic Bcl2 Family Membersmentioning

confidence: 99%

BCL2 family in DNA damage and cell cycle control

2006

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Individual BCL2 family members couple apoptosis regulation and cell cycle control in unique ways. Antiapoptotic BCL2 and BCL-x L are antiproliferative by facilitating G0. BAX is proapoptotic and accelerates S-phase progression. The dual functions in apoptosis and cell cycle are coordinately regulated by the multi-domain BCL2 family members (MCL-1) and suggest that survival is maintained at the expense of proliferation. The role of BH3-only molecules in cell cycle is more variable. BAD antagonizes both the cell cycle and antiapoptotic functions of BCL2 and BCL-x L through BH3 binding. BID has biochemically separable functions in apoptosis and S-phase checkpoint, determined by posttranslational modification. p53-induced PUMA is known only to have apoptotic function. Inhibition of apoptosis is oncogenic, whereas promotion of cell cycle arrest is tumor suppressive. Paradoxically, selected BCL2 family members can be both oncogenic and tumor suppressive. Which of the dual functions predominates is lineage specific and context dependent.

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“…[9][10][11][12][13][14][15] Bcl-W −/− mice have impaired spermatogenesis. 16,17 A1 remains the only pro-survival BCL-2 family member for which a knockout mouse strain has not been developed. A1 was first discovered as a GM-CSF-inducible gene with significant sequence similarity to BCL-2 and MCL-1, 18 and its human homologue BFL-1 was later identified in fetal liver.…”

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confidence: 99%

Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment

et al. 2017

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The pro-survival proteins of the BCL-2 family regulate the survival of all cells, and genetic deletion models for these proteins have revealed which specific BCL-2 family member(s) is/are critical for the survival of particular cell types. A1 is a pro-survival BCL-2-like protein that is expressed predominantly in haematopoietic cells, and here we describe the characterisation of a novel mouse strain that lacks all three functional isoforms of A1 (A1-a, A1-b and A1-d). Surprisingly, complete loss of A1 caused only minor defects, with significant, although relatively small, decreases in γδTCR T cells, antigen-experienced conventional as well as regulatory CD4 T cells and conventional dendritic cells (cDCs). When examining these cell types in tissue culture, only cDC survival was significantly impaired by the loss of A1. Therefore, A1 appears to be a surprisingly redundant pro-survival protein in the haematopoietic system and other tissues, suggesting that its targeting in cancer may be readily tolerated. Cell Death and Differentiation (2017) 24, 534-545; doi:10.1038/cdd.2016.156; published online 13 Janaury 2017The pro-survival proteins of the BCL-2 family prevent apoptosis 1 and studies using gene-targeted mice have revealed which cell types rely on which pro-survival protein for their survival. For example, Bcl-2 −/− mice exhibit thymic and splenic atrophy, a loss of fur pigment and die~30 days post birth from polycystic kidney disease, attributable to excess lymphocyte, melanocyte and renal epithelial cell apoptosis, respectively. 2-4 Bcl-X −/− mice die before E14.5 of embryonic development because of aberrant death of erythroid and neuronal cells. 5 The generation of chimaeric or tissue-specific Bcl-X −/− revealed a critical role for BCL-XL in the survival of developing lymphocytes 5 and platelets. 6,7 Mcl-1 −/− embryos die before implantation (E3.5), 8 but conditional Mcl-1 deletion models have demonstrated an essential role for MCL-1 in the survival of haematopoietic stem cells, lymphocytes, neurons and cardiomyocytes. 9-15 Bcl-W −/− mice have impaired spermatogenesis. 16,17 A1 remains the only pro-survival BCL-2 family member for which a knockout mouse strain has not been developed. A1 was first discovered as a GM-CSF-inducible gene with significant sequence similarity to BCL-2 and MCL-1, 18 and its human homologue BFL-1 was later identified in fetal liver. 19 Overexpression of A1 protected an IL-3-dependent cell line from growth factor deprivation-induced apoptosis, thus demonstrating its pro-survival function. 20 In mice, A1 expression is restricted to the haematopoietic compartment. 18 Human BFL-1 expression is more widespread, but also predominantly haematopoietic. 21 A1 can be upregulated by NF-κB signalling, and it has been proposed that A1/BFL-1 is important for the survival of several activated immune cell subsets through stimulation of antigen or cytokine receptors. [22][23][24][25] Studies of A1 in mice are complicated by the presence of multiple isoforms that are the result of gene duplication ev...

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Apoptosis regulator Bcl-w is essential for spermatogenesis but appears otherwise redundant

Cited by 299 publications

References 43 publications

Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages

Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages

BCL2 family in DNA damage and cell cycle control

Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment

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