Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation

Abstract

Ultraviolet (UV) irradiation of

Endoplasmic reticulum stress-induced cell death mediated by the proteasome

“…22 Pro-apoptotic functions of the proteasome have been described in several instances including the constitutive death of neutrophils as well as NGF withdrawal, DNA damage, glucocorticoid treatment and reduced extracellular potassium. [23][24][25][26][27] Additionally, the proteasome has been implicated in the early stages of wallerian degeneration after axotomy. 28 In response to DNA damage, the large Bcl-2 homology domain-only protein Mule/ARF-BP1 was shown to ubiquitylate Mcl-1 -an anti-apoptotic Bcl-2 family member -thereby causing its degradation via the proteasome.…”

Unraveling MCL-1 degradation

“…16 In contrast, Green and colleagues suggest a growth factor-dependent regulation of MCL-1 stability. 23 Perhaps, the difference in cell types lie at the heart of this discrepancy; in growth factor-dependent cell lines, the regulation of MCL-1 levels may be under a different level of control than in fibroblasts.…”

“…16 Wang and colleagues have demonstrated that in response to genotoxic stress the proteasome-dependent elimination of MCL-1 is required for downstream apoptotic events including BAX and BAK oligomerization, cytochrome c release, and caspase activation. Treatment of cells with proteasome inhibitors could block the elimination of MCL-1 and prolong survival.…”

“…Interestingly, in these studies the degradation of MCL-1 appeared to be constitutive as the half-life of MCL-1 was the same in the presence or absence of the death stimuli. 16 To identify the pathway leading to MCL-1 poly-ubiquitylation, Wang and colleagues utilized a biochemical purification strategy to purify a novel E3 ubiquitin ligase (MULE) required for MCL-1 degradation. 17 Expression of a mutant MCL-1, in which the targets of ubiquitin ligation were mutated, or small hairpin RNA-mediated 'knock-down' of MULE increased MCL-1 levels and promoted survival in response to genotoxic death stimuli.…”

Apoptosis in the development of the immune system

“…MCL-1 protein is unique among antiapoptotic BCL-2 family members in that it has a short half-life and is the target of the ubiquitin/proteasome-dependent degradation pathway. 42 This degradation may be regulated by cytokines as growth factor withdrawal resulted in MCL-1 phosphorylation by glycogen synthase kinase-3b and enhanced ubiquitinylation. 43 These data suggest that during lymphocyte development, MCL-1 phosphorylation may play a critical role in regulating its protective function and expression, but this hypothesis still needs to be tested in vivo.…”