Tamoxifen-induced activation of p21Waf1/Cip1 gene transcription is mediated by Early Growth Response-1 protein through the JNK and p38 MAP kinase/Elk-1 cascades in MDA-MB-361 breast carcinoma cells

Chang Gun Kim, Byeong Hyeok Choi, Sang Wook Son, Seong Joon Yi, Soon Young Shin, Young Han Lee

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    33 Citations (Scopus)

    Abstract

    Tamoxifen (TAM) is a synthetic non-steroidal anti-estrogen compound that is widely used as an effective chemotherapeutic agent for treatment and prevention of breast cancer. Unfortunately, prolonged treatment with TAM causes TAM-responsive tumors to become TAM resistant through an as-yet-unknown mechanism. To develop novel anti-breast cancer agents that are therapeutically superior to TAM, we must first fully understand the biological effects of TAM. In this study, we found that TAM treatment of MDA-MB-361 breast cancer cells activated p21Waf1/Cip1 gene transcription independently of p53. Furthermore, TAM-induced p21Waf1/Cip1 promoter activity was enhanced by transient expression of the gene encoding Early Growth Response-1 (Egr-1) protein, a transcription factor that plays an important role in cell growth and differentiation. The TAM-induced p21Waf1/Cip1 promoter activity was blocked by the expression of small interfering RNA (siRNA) targeted to Egr-1 mRNA. In addition, induction of Egr-1 expression by TAM occurred at the transcriptional level via Ets-domain transcription factor Elk-1 through the JNK and p38 mitogen-activated protein (MAP) kinase pathways. Inhibition of the JNK and p38 MAP kinase signals inhibited Egr-1-mediated p21Waf1/Cip1 promoter activity. We conclude that TAM stimulation of p21Waf1/Cip1 gene transcription in MDA-MB-361 cells depends largely on Elk-1-mediated Egr-1 expression induced by activation of the JNK and p38 MAP kinase pathways.

    Original languageEnglish
    Pages (from-to)1290-1300
    Number of pages11
    JournalCellular Signalling
    Volume19
    Issue number6
    DOIs
    Publication statusPublished - 2007 Jun

    Bibliographical note

    Funding Information:
    This work was supported by a Grant 0620400-1 from the National Cancer Center, Korea (Y.H.L.), by a grant (M103KV010022-06K2201-02210) from Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology, the Republic of Korea (Y.H.L), and by grant No. R01-2006-000-10950-0(2006) from the Basic Research Program of the Korea Science and Engineering Foundation (S.Y.S.).

    Keywords

    • Egr-1
    • Mitogen-activated protein kinase
    • Tamoxifen
    • p21

    ASJC Scopus subject areas

    • Cell Biology

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