Caspase 3 inactivation to suppress Fas-mediated apoptosis: identification of binding domain with p21 and ILP and inactivation machinery by p21

Suzuki, Atsushi; Tsutomi, Yumi; Miura, Masayuki; Akahane, Kouichi

doi:10.1038/sj.onc.1202409

Cited by 135 publications

(129 citation statements)

References 22 publications

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“…However, we cannot discern whether p21 suppression of p16-induced apoptosis is the result of a direct antiapoptotic function of p21 or whether suppression of apoptosis is dependent on inhibition of CDK2. Since p21 protein can interfere with proapoptotic pathways at different levels, 43 further investigation is needed to elucidate specific mediators of p16-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

The fate of pancreatic tumor cell lines following p16 overexpression depends on the modulation of CDK2 activity

et al. 2004

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Restitution of lost tumor-suppressor activities may be a promising strategy to target specifically cancer cells. However, the action of ectopically expressed tumor-suppressor genes depends on genetic background of tumoral cells. Ectopic expression of p16 INK4a induces either cell cycle arrest or apoptosis in different pancreatic cancer cell lines. We examined the molecular mechanisms mediating these two different cellular responses to p16 overexpression. Ectopic expression of p16 leads to G1 arrest in NP-9 cells by redistributing p21/p27 CKIs and inhibiting cyclin-dependent kinase CDK2 activity. In contrast, in NP-18 cells cyclin E (CycE)/ CDK2 activity is significantly higher and is not downregulated by p16-mediated redistribution of p21/p27. Moreover, inhibition of CDK4 activity with fascaplysine, which does not affect CycE/ CDK2 activity, reduces pocket protein phosphorylation in both cell lines, but fails to induce growth arrest. Like overexpression of p16, fascaplysine induces apoptosis in NP-18 cells, suggesting that inhibition of D-type cyclin/CDK activity in cells with high levels of CycE/CDK2 activity activates an apoptotic pathway. Inhibition of CycE/CDK2 activity via ectopic expression of p21 in NP-18 cells overexpressing p16 induces growth arrest and prevents p16-mediated apoptosis. Accordingly, silencing of p21 expression by using small interfering RNA switches the fate of p16-expressing NP-9 cells from cell cycle arrest to apoptosis. Our data suggest that, after CDK4/6 inactivation, the fate of pancreatic tumor cells depends on the ability to modulate CDK2 activity.

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Section: Discussionmentioning

confidence: 99%

The fate of pancreatic tumor cell lines following p16 overexpression depends on the modulation of CDK2 activity

et al. 2004

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“…Indeed, p21 waf1 nuclear localization promotes growth arrest, while its cytoplasmic accumulation prevents apoptosis through the interaction and the suppression of pro-caspase-3. 35 Because of these opposite roles of p21 waf1 depending on its subcellular localization and to the observed miR-128-2-dependent antiapoptotic effect, we analyzed p21 waf1 subcellular localization upon miR-128-2 overexpression. We observed, by cell fractionation ( Figure 5f) and immunofluorescence (Figure 5g), that p21 waf1 accumulates in the cytoplasm of both H1299 and A459 cell lines following miR-128-2 exogenous expression.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function

Donzelli¹,

et al. 2011

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p53 mutations have profound effects on non-small-cell lung cancer (NSCLC) resistance to chemotherapeutic treatments. Mutant p53 proteins are usually expressed at high levels in tumors, where they exert oncogenic functions. Here we show that p53R175H, a hotspot p53 mutant, induces microRNA (miRNA)-128-2 expression. Mutant p53 binds to the putative promoter of miR128-2 host gene, ARPP21, determining a concomitant induction of ARPP21 mRNA and miR-128-2. miR-128-2 expression in lung cancer cells inhibits apoptosis and confers increased resistance to cisplatin, doxorubicin and 5-fluorouracyl treatments. At the molecular level, miR-128-2 post-transcriptionally targets E2F5 and leads to the abrogation of its repressive activity on p21 waf1 transcription. p21 waf1 protein localizes to the cytoplasmic compartment, where it exerts an anti-apoptotic effect by preventing pro-caspase-3 cleavage. This study emphasizes miRNA-128-2 role as a master regulator in NSCLC chemoresistance. Cell Death and Differentiation (2012) 19, 1038-1048 doi:10.1038/cdd.2011 published online 23 December 2011 Mutations in the TP53 gene are the most frequent type of gene-specific alterations in human cancers. 1 The majority of cancer-associated mutations in TP53 gene are missense mutations that reside mainly in the exons encoding for p53 DNA-binding domain. 2 These mutations frequently result in full-length mutant p53 proteins incapable of activating p53 target genes and suppressing tumorigenesis. 3 Most TP53 mutations can be classified into two main categories according to their effect on the thermodynamic stability of the p53 protein. 4 These two mutation categories are commonly referred to as DNA-contact and conformational mutations. The first group includes mutations in residues directly involved in DNA binding, such as R248Q and R273H. The second group comprises mutations that cause local (such as R249S and G245S) or global (such as R175H and R282W) conformational distortions.Besides losing their wild-type (wt) activities, mutant p53 proteins have also dominant-negative effects that inactivate wt p53 protein expressed from the remaining wt allele. Moreover, some mutant p53 forms also acquire new oncogenic properties -'gain of function' -that overrule those due to loss of wt p53 activity by gene deletion. 5-7 These properties range from enhanced proliferation in culture and resistance to a variety of anticancer drugs commonly used in the clinical practice, to increased tumorigenicity in vivo. [8][9][10] Recent work indicates that mutant p53 protein can augment in vitro and in vivo cell migration and invasion. 11 Fontemaggi et al. 12 showed that mutant p53 increases also the angiogenic potential of cancer cells by modulating, at the transcriptional level, Id4 expression.The existing knowledge regarding the molecular mechanisms whereby mutant p53 regulates gene expression is still lacking. To date, we can depict the three following molecular scenarios to explain gain-of-function of mutant p53 proteins: (i) mutant p53 binds to the promoter of ...

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“…Cell Death and Differentiation Procaspase 3/p21 complex by ATP and PKA A Suzuki et al the NH 2 -terminal sequence of the zymogen form of caspase 3 (procaspase 3 and see 10,11 ). As a result of its interaction with p21, the p3 cleavage site on procaspase 3 is blocked from cytoplasmic serine proteinase.…”

Section: Discussionmentioning

confidence: 99%

“…10 ± 12 Caspase 3 is inactivated as a result of masking its p3-cleavage site. 11 In addition, activated caspase 3 is inactivated by the IAP family member ILP. 10,11,13,14 Through this two step mechanism, caspase 3 is inactivated endogenously in cells.…”

Section: Introductionmentioning

confidence: 99%

Procaspase 3/p21 complex formation to resist Fas-mediated cell death is initiated as a result of the phosphorylation of p21 by protein kinase A

et al. 2000

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Caspase 3 is an essential factor for Fas-mediated cell death and exists endogenously in cells where its activation is suppressed by p21 and ILP. Inside the cell, procaspase 3 interacts with p21 on mitochondria. In the present study, we investigated the molecular basis for procaspase 3/p21 complex formation. During Fas-mediated cell death, mitochondria are damaged, accompanied by decreased mitochondrial membrane-potential and decreased intracellular ATP levels. This mitochondrial damage occurs before an estrangement of the procaspase 3/p21 complex, and we demonstrate that intracellular ATP-deprivation also initiates an estrangement of procaspase 3/p21 complex formation and accelerates Fas-mediated cell death. In addition, our current results revealed that the phosphorylated p21 by PKA interacts with procaspase 3. Here, we report that the mitochondrial role, especially for ATP synthesis, and PKA are necessary for the procaspase 3/p21 complex formation to resist Fas-mediated cell death. Cell Death and Differentiation (2000) 7, 721 ± 728.

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Caspase 3 inactivation to suppress Fas-mediated apoptosis: identification of binding domain with p21 and ILP and inactivation machinery by p21

Cited by 135 publications

References 22 publications

The fate of pancreatic tumor cell lines following p16 overexpression depends on the modulation of CDK2 activity

The fate of pancreatic tumor cell lines following p16 overexpression depends on the modulation of CDK2 activity

MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function

Procaspase 3/p21 complex formation to resist Fas-mediated cell death is initiated as a result of the phosphorylation of p21 by protein kinase A

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