The Combined Functions of Proapoptotic Bcl-2 Family Members Bak and Bax Are Essential for Normal Development of Multiple Tissues

Lindsten, Tullia; Ross, Andrea J.; King, Alison; Zong, Wei Xing; Rathmell, Jeffrey C.; Shiels, Helena; Ulrich, Eugen; Waymire, Katrina G.; Mahar, Patryce L.; Frauwirth, Kenneth A.; Chen, Yifeng; Wei, Michael C.; Eng, Vicki M.; Adelman, David M.; Simon, M. Celeste; Ma, Averil; Golden, Jeffrey A.; Evan, Gérard I.; Korsmeyer, Stanley J.; MacGregor, Grant R.; Thompson, Craig B.

doi:10.1016/s1097-2765(00)00136-2

Cited by 1,312 publications

(1,180 citation statements)

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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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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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“…48,54 However, the absence of multi-domain BAX or BAK results in prominent inhibition of apoptosis emanating from both intrinsic and extrinsic pathways with resultant abrogation of homeostatic control. 79 Despite this potent perturbation of apoptosis, to date, bax À/À or bak mice do not progress to malignancy. BAX deficiency and BAX overexpression can synergize with other oncogenes, and like BCL2, BAX has dual roles to either enhance or inhibit tumorigenesis depending on the genetic context.…”

Section: Relationship Between Bcl2 Family Cell Cycle and Antiapoptosimentioning

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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“…[18][19][20] This is an interesting observation because in other cell types the expression of both Bax and Bak must be lost to prevent cell death induced by survival factor withdrawal. 21,22 This difference may be related to the fact that postnatal sympathetic neurons, hippocampal neurons and CGNs cultured in vitro exclusively express N-Bak, a neuron-specific splice variant of Bak, which is a BH3-only protein lacking the BH1 and BH2 domains of full-length Bak. 23,24 Thus, in vitro these cells only express one multidomain proapoptotic protein (Bax) in contrast to other cell types, which express both Bax and fulllength Bak.…”

Section: Ngf Withdrawal-induced Death Requires Transcription and Invomentioning

confidence: 99%

BH3-only proteins: key regulators of neuronal apoptosis

Ham

Towers²,

Gilley³

et al. 2005

Cell Death Differ

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The molecular mechanisms of neuronal apoptosis have been intensively studied because a considerable amount of apoptosis occurs during the normal development of the mammalian nervous system. This death is important for establishing neuronal populations of the correct size and for ensuring that neurons that contact inappropriate targets are eliminated. 1,2 A second reason for the interest in this area is that there is increasing evidence that apoptosis is one of the mechanisms of neuronal death following acute injuries to the nervous system, such as stroke or traumatic brain injury, and neurons often die by apoptosis in cell culture and animal models of chronic human neurodegenerative disorders. 2 The aim of this article is to review recent work on the function and regulation of the BH3-only subfamily of Bcl-2 proteins in neurons, with an emphasis on studies with sympathetic neurons, cerebellar granule neurons (CGNs) and motoneurons, the best studied in vitro models of neuronal apoptosis, and work that has involved the analysis of neurons from mutant mice.

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The Combined Functions of Proapoptotic Bcl-2 Family Members Bak and Bax Are Essential for Normal Development of Multiple Tissues

Cited by 1,312 publications

References 46 publications

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

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

BCL2 family in DNA damage and cell cycle control

BH3-only proteins: key regulators of neuronal apoptosis

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