Abstract
We previously reported that the activation of p21WAF1/Cip1 transcription by histone deacetylase inhibitor apicidin was mediated through Sp1 sites and pointed to the possible participation of protein kinase C (PKC). In this study, we investigated the role and identity of the specific isoforms of PKC involved and identified phosphatidylinositol 3-kinase (PI 3-kinase) as an upstream effector in HeLa cells. Using an isoform-specific pharmacological inhibitor of PKC, a PKCɛ dominant-negative mutant, and antisense oligonucleotide to inhibit PKCɛ specifically, we found that among PKC isoforms, PKCɛ was required for the p21WAF1/Cip1 expression by apicidin. In addition to PKCɛ, PI 3-kinase appeared to participate in the activation of p21WAF1/Cip1 promoter by apicidin, since inactivation of PI 3-kinase either by transient expression of dominant-negative mutant of PI 3-kinase or its specific inhibitors, LY294002 and wortmannin, attenuated the activation of p21WAF1/Cip1 promoter and p21WAF1/Cip1 protein expression by apicidin. Furthermore, membrane translocation of PKCɛ in response to apicidin was blocked by the PI 3-kinase inhibitor, indicating the role of PI 3-kinase as an upstream molecule of PKCɛ in the p21WAF1/Cip1 promoter activation by apicidin. However, the p21WAF1/Cip1 expression by apicidin appeared to be independent of the histone hyperacetylation, since apicidin-induced histone hyperacetylation of p21WAF1/Cip1 promoter region was not affected by inhibition of PI 3-kinase and PKC, suggesting that the chromatin remodeling through the histone hyperacetylation alone might not be sufficient for the expression of p21WAF1/Cip1 by apicidin. Taken together, these results suggest that the PI 3-kinase–PKCɛ signaling pathway plays a pivotal role in the expression of the p21WAF1/Cip1 by apicidin.
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Abbreviations
- HDAC:
-
histone deacetylase
- PKC:
-
protein kinase C
- Cdk:
-
cyclin-dependent kinase
- TSA:
-
trichostatin A
- NaB:
-
sodium butyrate
- SAHA:
-
suberoylanilide hydroxamic acid
- PDBu:
-
phorbol-dibutyrate
- ERK:
-
extracellular-regulated protein kinase
- PKA:
-
protein kinase A
- MAPK:
-
mitogen-activated protein kinase
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Acknowledgements
This work was supported by Grant No. R01-2002-000-00213-0 from the Basic Research Program of the Korea Science and Engineering Foundation. We thank Dr Y Sowa (Kyoto Prefectural University of Medicine) for giving us the pWP101 reporter gene, Dr G Thiel (Medical Biochemistry and Molecular Biochemistry, University of the Saarland Medical Center) for delta-Sp1, Dr A Toker (Boston Biomedical Research Inst., Harvard Medical School) for PKCɛ-KW, and Dr M Wymann (Institute of Biochemistry, University of Fribourg, Switzerland) for PI3K-KR.
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Kim, Y., Han, JW., Woo, Y. et al. Expression of p21WAF1/Cip1 through Sp1 sites by histone deacetylase inhibitor apicidin requires PI 3-kinase–PKCε signaling pathway. Oncogene 22, 6023–6031 (2003). https://doi.org/10.1038/sj.onc.1206875
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DOI: https://doi.org/10.1038/sj.onc.1206875
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