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Role of p21 in SP600125-induced cell cycle arrest, endoreduplication, and apoptosis

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Abstract

The anti-cancer effect of the c-Jun N-terminal kinase (JNK) inhibitor SP600125 has been well evaluated in human cancer cells. However the role of p21 in SP600125-mediated G2/M distribution is not fully understood. Our results showed that the transcriptional activation of p21 by SP600125 is mediated through the proximal regions of multiple Sp1 sites in the p21 promoter following ERK-dependent phosphorylation of Sp1. In this process, p21 induces endoreduplication through the inhibition of cyclin E/Cdk2 activity at 24 h but does not directly regulate cyclin B1/Cdc2 activity. Furthermore, SP600125 induces the phosphorylation of p21 at Thr 145 through the PI3K/Akt pathway. Akt-mediated phosphorylation of p21 and protection of apoptosis are completely abolished by inhibitors of PI3K and Akt. In summary using time points, we identified the dual functions of p21 as an inhibitor of cell-cycle progression at 24 h and as an anti-apoptotic factor at 48 h.

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Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0016098). We greatly appreciate the gift of HCT116 p21+/+ and HCT116 p21−/− cells from Prof. Deung Y. Shin (Dankook University College of Medicine, Chungnam, Republic of Korea).

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  1. Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju, 690-756, Republic of Korea

    Dong-Oh Moon & Gi-Young Kim

  2. Department of Biochemistry, College of Oriental Medicine, Dongeui University, Busan, 614-054, Republic of Korea

    Yung Hyun Choi

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  1. Dong-Oh Moon
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Correspondence to Yung Hyun Choi or Gi-Young Kim.

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Moon, DO., Choi, Y.H. & Kim, GY. Role of p21 in SP600125-induced cell cycle arrest, endoreduplication, and apoptosis. Cell. Mol. Life Sci. 68, 3249–3260 (2011). https://doi.org/10.1007/s00018-011-0626-5

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  • DOI: https://doi.org/10.1007/s00018-011-0626-5

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