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

Suzuki, Atsushi; Kawano, Hirokazu; Hayashida, Midori; Hayasaki, Yayoi; Tsutomi, Yumi; Akahane, Kouichi

doi:10.1038/sj.cdd.4400706

Cited by 76 publications

(59 citation statements)

References 35 publications

(49 reference statements)

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“…Caspase activity can be inhibited by a range of cellular processes, such as high expression of Melanoma Inhibitor of Apoptosis Protein, overexpression of survivin, or even by binding of p21 WAF1 to procaspase-3. [43][44][45] T-ALL PDX cells were also sensitive to the death inducing effects of vorinostat, as determined by significantly lower IC 50 values compared to BCP-ALL PDXs. In comparison, the p21 WAF1 -defective T-ALL and p21 WAF1 -functional BCP-ALL PDXs demonstrated generally similar sensitivities to the p53-inducing agents, etoposide and nutlin-3.…”

Section: Discussionmentioning

confidence: 99%

p21^WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

Davies¹,

Hogarth

MacKenzie³

et al. 2015

Cell Cycle

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Keywords: childhood acute lymphoblastic leukemia, etoposide, p21 WAF1 , patient derived xenograft models, terameprocol, vorinostat p21 WAF1 is a well-characterized mediator of cell cycle arrest and may also modulate chemotherapy-induced cell death. The role of p21 WAF1 in drug-induced cell cycle arrest and apoptosis of acute lymphoblastic leukemia (ALL) cells was investigated using p53-functional patient-derived xenografts (PDXs), in which p21 WAF1 was epigenetically silenced in T-cell ALL (T-ALL), but not in B-cell precursor (BCP)-ALL PDXs. Upon exposure to diverse cytotoxic drugs, T-ALL PDX cells exhibited markedly increased caspase-3/7 activity and phosphatidylserine (PS) externalization on the plasma membrane compared with BCP-ALL cells. Despite dramatic differences in apoptotic characteristics between T-ALL and BCP-ALL PDXs, both ALL subtypes exhibited similar cell death kinetics and were equally sensitive to p53-inducing drugs in vitro, although T-ALL PDXs were significantly more sensitive to the histone deacetylase inhibitor vorinostat. Transient siRNA suppression of p21 WAF1 in the BCP-ALL 697 cell line resulted in a moderate depletion of the cell fraction in G1 phase and marked increase in PS externalization following exposure to etoposide. Furthermore, stable lentiviral p21 WAF1 silencing in the BCP-ALL Nalm-6 cell line accelerated PS externalization and cell death following exposure to etoposide and vorinostat, supporting previous findings. Finally, the Sp1 inhibitor, terameprocol, inhibited p21 WAF1 expression in Nalm-6 cells exposed to vorinostat and also partially augmented vorinostat-induced cell death. Taken together, these findings demonstrate that p21 WAF1 regulates the early stages of drug-induced apoptosis in ALL cells and significantly modulates their sensitivity to vorinostat.

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Section: Discussionmentioning

confidence: 99%

p21^WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

Davies¹,

Hogarth

MacKenzie³

et al. 2015

Cell Cycle

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“…[49][50][51][52] p21 Cip1/WAF1 has also been shown to inhibit Fasmediated apoptosis by forming a complex with procaspase-3. 53 However, p21 Cip1/WAF1 has been shown to induce apoptosis or even found to be indispensable for apoptosis. 54 …”

Section: Discussionmentioning

confidence: 99%

Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1

et al. 2005

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Histone deacetylases (HDACs) 1 and 2 share a high degree of homology and coexist within the same protein complexes. Despite their close association, each possesses unique functions. We show that the upregulation of HDAC2 in colorectal cancer occurred early at the polyp stage, was more robust and occurred more frequently than HDAC1. Similarly, while the expression of HDACs1 and 2 were increased in cervical dysplasia and invasive carcinoma, HDAC2 expression showed a clear demarcation of high-intensity staining at the transition region of dysplasia compared to HDAC1. Upon HDAC2 knockdown, cells displayed an increased number of cellular extensions reminiscent of cell differentiation. There was also an increase in apoptosis, associated with increased p21Cip1/WAF1 expression that was independent of p53. These results suggest that HDACs, especially HDAC2, are important enzymes involved in the early events of carcinogenesis, making them candidate markers for tumor progression and targets for cancer therapy.

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“…In fact, "oncoprotein"-like properties of p21 such as inhibition of apoptosis or activation of secretion of mitogens are described in the literature. [51][52][53] Elevated p21 protein levels have been observed in various aggressive tumors and phosphorylation of p21 by the survival kinase AKT/PKB leads to enhanced p21 stability and subsequently to increased resistance to taxol-mediated toxicity in glioblastoma cells. 54 Moreover, p21 overexpression has been described as an early event in the development of pancreatic neoplasia 55 and was also observed in breast tumors.…”

confidence: 99%

FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

Martin¹,

Kleiber²,

Wixler³

et al. 2007

Cell Cycle

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© 2 0 0 7 L A N D E S B I O S C I E N C E . D O N O T D I S T R I B U T E .[Cell Cycle 6:14, 1779-1788, 15 ABSTRAcTThe transcriptional cofactor FHL2 interacts with a broad variety of transcription factors and its expression is often deregulated in various types of cancer. Here we analyzed for the first time the molecular function of FHL2 in breast cancer. FHL2 is overexpressed in almost all human mammary carcinoma samples tested but not in normal breast tissues and only low levels of FHL2 expression were present in four premalignant ductal carcinoma in situ (DCIS). Cell cycle analysis revealed an upregulation of endogenous FHL2 towards G 2 /M in MDA-MB 231 cells and an accelerated G 2 /M transition when FHL2 expression was suppressed in these cells. In search for G 2 /M specific target genes regulated by FHL2, we found that expression of the cell cycle inhibitor p21 Cip1/Waf1 (hereafter p21) is dependent on FHL2 in MDA-MB 231 breast cancer cells. Downregulation of FHL2 by shRNA abrogated the cell cycle dependent upregulation of p21 as well as the induction of p21 in response to treatment with the DNA damaging agent doxorubicin. FHL2-dependent p21 expression occurs in a p53-independent manner and p21 expression can be downregulated by specific inhibition of mitogen-activated protein kinases (MAPKs), implicating an involvement of MAPK signaling in this regulation. Analysis of FHL2 contribution to the MAPK signaling identified FHL2 as an important downstream effector of MAPKs in breast cancer cells, capable of transactivating endogenous AP1 target genes as well as AP1 dependent reporter genes. Finally, downregulation of FHL2 reduces the ability of MDA-MB 231 cells to form colonies in soft agar, while FHL2 overexpression enhances colony formation of breast cancer cells. Thus, our findings indicate that overexpression of the transcriptional cofactor FHL2 contributes to breast cancer development by mediating transcriptional activation of MAPK target genes known to be involved in cancer progression, such as p21.

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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

Cited by 76 publications

References 35 publications

p21^WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

p21^WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1

FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

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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

Cited by 76 publications

References 35 publications

p21WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

p21WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1

FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

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p21^WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

p21^WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia