Sustained Activation of the JNK Cascade and Rapamycin-Induced Apoptosis Are Suppressed by p53/p21Cip1

Huang, Shile; Shu, Lili; Dilling, Michael B.; Easton, John; Harwood, Franklin C.; Ichijo, Hidenori; Houghton, Peter J.

doi:10.1016/s1097-2765(03)00180-1

Cited by 220 publications

(191 citation statements)

References 36 publications

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“…Among several p53 downstream molecules, p21 has been reported to suppress the activation of JNK (Huang et al, 2003;Watanabe et al, 2006). We established two stable clones of RT112 transfected with p21siRNA vector (RT112 p21siRNA-8 and -12) and investigated JNK status and susceptibility to CDDP and triptolide.…”

Section: Resultsmentioning

confidence: 99%

Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3β with p53

et al. 2008

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To improve conventional chemotherapeutic efficacy, a combination use of traditional medicines is effective but detailed mechanisms have been rarely elucidated. In the this study, we attempted to clarify how triptolide (PG490), an oxygenated diterpene derived from a Chinese herb, enhances the cisplatin (CDDP)-induced cytotoxicity in urothelial cancer cells. Our results showed that a combined CDDP/triptolide therapy induced apoptosis in urothelial cancer cell lines with wild-type p53, but not in those with mutant-type p53 or normal human urothelium. As the mechanism, triptolide suppressed CDDP-induced p53 transcriptional activity, leading to p21 attenuation, which promoted apoptosis via the activation of c-Jun N-terminal kinase (JNK) and Bax. We further demonstrated that the functional regulation of p53 by triptolide was mediated by an intranuclear association of p53 with glycogen synthase kinase-3b (GSK3b), which was inactivated by protein kinase C (PKC). This modulation of the PKC-GSK3b axis by triptolide was observed in a cancer-specific manner. A mouse xenograft model also showed that a combined CDDP/triptolide therapy completely suppressed tumor growth without any side effects. We expect that cancer-specific enhancement of CDDP-induced cytotoxicity with triptolide may effectively overcome the resistance to a CDDP-based conventional chemotherapy as a treatment for urothelial cancer.

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Section: Resultsmentioning

confidence: 99%

Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3β with p53

et al. 2008

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“…We observed the induction and enhancement of p53-independent apoptosis by vanadate in irradiated HL60, U937, and MOLT/p53KD cells (especially MOLT/p53KD-2) (Figure 4b and e). One explanation for this effect may be that the SAPK/JNK-dependent apoptotic pathway is augmented, because the loss of p53 function potentiates this pathway 32 and vanadate enhances it (Figure 4c). Such augmentation, like the upregulation of SAPK/JNK phosphorylation, was observed in these cells when they were treated with vanadate alone (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Sodium orthovanadate suppresses DNA damage-induced caspase activation and apoptosis by inactivating p53

et al. 2005

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We previously reported that p42/SETb is a substrate for caspase-7 in irradiated MOLT-4 cells, and that treating the cells with sodium orthovanadate (vanadate) inhibits p42/SETb's caspase-mediated cleavage. Here, we initially found that the inhibitory effect of vanadate was due to the suppression of caspase activation but not of caspase activity. Further investigations revealed that vanadate suppressed upstream of apoptotic events, such as the loss of mitochondrial membrane potential, the conformational change of Bax, and p53 transactivation, although the accumulation, total phosphorylation, and phosphorylation of six individual sites of p53 were not affected. Importantly, vanadate suppressed p53-dependent apoptosis, but not p53-independent apoptosis. Finally, gel-shift and chromatin immunoprecipitation assays conclusively demonstrated that vanadate inhibits the DNA-binding activity of p53. Vanadate is conventionally used as an inhibitor of protein tyrosine phosphatases (PTPs); however, we recommend that the influence of vanadate not only on PTPs but also on p53 be considered before using it.

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“…Cytoplasmic p21 can interact with, and thereby inactivate, multiple pro-apoptotic proteins such as SAPK (also known as JNK) 91 , pro-caspase 3 (REF. 92) and ASK1 (apoptosissignal-regulating kinase 1, also known as mitogenactivated protein kinase kinase kinase 5 (MAP3K5)) 93,94 . Cytoplasmic localization of p21 has been reported to correspond with a poor clinical outcome of patients with breast cancer 95,96 , which could therefore be explained by the observation that besides losing its CDK-inhibitory function, cytoplasmic p21 also gains anti-apoptotic functions 93,94 .…”

Section: Is P21 Required For Oncogenic Transformation?mentioning

confidence: 99%

KLF4, p21 and context-dependent opposing forces in cancer

2005

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| Krüppel-like factors are transcriptional regulators that influence several cellular functions, including proliferation. Recent studies have shown that one family member, KLF4, can function both as a tumour suppressor and an oncogene. The ability of KLF4 to affect the levels of expression of the cell-cycle regulator p21 seems to be involved, in that this protein might function as a switch that determines the outcome of KLF4 signalling. Is this role of p21 restricted to KLF4, or does p21 represent a nodal point for signals from multiple other factors with opposing functions in cancer?

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Sustained Activation of the JNK Cascade and Rapamycin-Induced Apoptosis Are Suppressed by p53/p21Cip1

Cited by 220 publications

References 36 publications

Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3β with p53

Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3β with p53

Sodium orthovanadate suppresses DNA damage-induced caspase activation and apoptosis by inactivating p53

KLF4, p21 and context-dependent opposing forces in cancer

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