Proteolytic Cleavage of the mdm2 Oncoprotein during Apoptosis

Chen, Lihong; Maréchal, Vincent; Moreau, Jacques; Levine, Arnold J.; Chen, Jiandong

doi:10.1074/jbc.272.36.22966

Cited by 119 publications

(133 citation statements)

References 58 publications

Supporting

Mentioning

126

Contrasting

Unclassified

Order By: Relevance

“…The evidence that eIF4G is degraded by a caspasemediated mechanism in response to a variety of apoptotic stimuli suggests that the initiation factor is a potential candidate to be added to the growing list of proteins that are cleaved by caspases (Martin and Green, 1995;Hale et al, 1996;Lavin et al, 1996;Chen et al, 1997;Widmann et al, 1998). However the e ects of the inhibitors Z-VAD.FMK and Z-DEVD.FMK are not su cient to indicate which caspase activity is responsible, or indeed to establish that these enzymes are the actual catalysts of eIF4G cleavage.…”

Section: Discussionmentioning

confidence: 99%

Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

1998

View full text Add to dashboard Cite

We have investigated the e ect of inducing apoptosis in BJAB and Jurkat cells on the cellular content of several polypeptide chain initiation factors. Serum deprivation results in inhibition of protein synthesis and induction of apoptosis in BJAB cells; at early times, there is selective degradation of polypeptide initiation factor eIF4G but no major losses of other key initiation factors. The disappearance of full length eIF4G is accompanied by the appearance of smaller forms of the protein, including a major product of approximately 76 kDa. Apoptosis induced by cycloheximide results in similar e ects. Both total cytoplasmic eIF4G and eIF4G associated with eIF4E are degraded with a half-life of 2 ± 4 h under these conditions. Treatment of serum-starved or cycloheximide-treated cells with Z-VAD.FMK or Z-DEVD.FMK, which inhibit caspases required for apoptosis, protects eIF4G from degradation and blocks the appearance of the ca. 76 kDa product. Exposure of BJAB cells to rapamycin rapidly inhibits protein synthesis but does not lead to acute degradation of eIF4G. In both BJAB and Jurkat cells induction of apoptosis with anti-Fas antibody or etoposide also results in the selective loss of eIF4G, which is inhibitable by Z-VAD.FMK. These data suggest that eIF4G is selectively targeted for cleavage as cells undergo apoptosis and is a substrate for proteases activated during this process.

show abstract

Section: Discussionmentioning

confidence: 99%

Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

1998

View full text Add to dashboard Cite

show abstract

“…Previous studies have identified many substrates of caspases that play a role in cell cycle progression, such as cyclin E (43), Cdc2 (44), Cdc27, Wee1 (45), pRb (46), and MDM2 (47). Cleavage of these substrates invariably caused their inactivation and was associated with apoptotic conditions.…”

Section: Discussionmentioning

confidence: 99%

Carboxyl-terminal Proteolytic Processing of CUX1 by a Caspase Enables Transcriptional Activation in Proliferating Cells

Truscott

Denault

Goulet

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Proteolytic processing at the end of the G 1 phase generates a CUX1 isoform, p110, which functions either as a transcriptional activator or repressor and can accelerate entry into S phase. Here we describe a second proteolytic event that generates an isoform lacking two active repression domains in the COOH terminus. This processing event was inhibited by treatment of cells with synthetic and natural caspase inhibitors. In vitro, several caspases generated a processed isoform that co-migrated with the in vivo generated product. In cells, recombinant CUX1 proteins in which the region of cleavage was deleted or in which Asp residues were mutated to Ala, were not proteolytically processed. Importantly, this processing event was not associated with apoptosis, as assessed by terminal dUTP nick end labeling assay, cytochrome c localization, poly(ADP-ribose) polymerase cleavage, and fluorescence-activated cell sorting. Moreover, processing was observed in S phase but not in early G 1 , suggesting that it is regulated through the cell cycle. The functional importance of this processing event was revealed in reporter and cell cycle assays. A recombinant, processed, CUX1 protein was a more potent transcriptional activator of several cell cycle-related genes and was able to accelerate entry into S phase, whereas mutants that could not be processed were inactive in either assay. Conversely, cells treated with the quinoline-Val Asp-2,6-difluorophenoxymethylketone caspase inhibitor proliferated more slowly and exhibited delayed S phase entry following exit from quiescence. Together, our results identify a substrate of caspases in proliferating cells and suggest a mechanism by which caspases can accelerate cell cycle progression.

show abstract

“…The mechanism of formation of p60(MDM2) is still unclear. However, Chen et al 34) reported that MDM2 was cleaved by an caspase 3-like enzyme, leading to the accumulation of MDM2 with apparent molecular weight 60 kDa, with loss of 361 amino acids. This truncated form of MDM2 could bind to p53, but failed to promote p53 degradation due to the lack of the ring finger domain at the C-terminus, thereby apparently stabilizing p53 in a dominant-negative fashion.…”

Section: Discussionmentioning

confidence: 99%