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  • Original Paper
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p53 and Egr-1 additively suppress transformed growth in HT1080 cells but Egr-1 counteracts p53-dependent apoptosis

Oncogene volume 18, pages 3633–3642 (1999)Cite this article

Abstract

The human fibrosarcoma cell line, HT1080, clone H4, was used to determine if the transformation suppressive functions of p53 and Egr-1 have the same underlying mechanism. This cell line expresses only mutant p53 and no detectable Egr-1. H4 clones stably expressing Egr-1 are less transformed in proportion to the level of Egr-1 expressed, acting through the induction of the TGFβ1 gene. Here, H4 cells and the highest Egr-1 expressing clone were transfected with a vector expressing normal human p53 to derive stable clones expressing p53. The expression of p53 in H4 cells inhibited transformed growth and reduced tumorigenicity. The effect of co-expression of both p53 and Egr-1 was additive, producing cell lines with 30% of normal growth rate and sevenfold reduced tumorigenicity compared with control lines. These results indicated that each factor may act independently by different pathways, although each additively increased the level of p21WAF1 cell cycle inhibitor. However, exposure of the H4-derived cells to UV-C irradiation produced contrasting effects. Cell cycle analyses showed that the presence of p53 was associated with loss of the G1 and S cells to apoptosis after irradiation. In contrast, the expression of Egr-1 increased entry into S/G2 phase of the cell cycle with little apoptosis via a mechanism involving elevated FAK and low caspase activities. Apoptosis was observed only in the cell lines that expressed no Egr-1, especially those expressing wt-p53, and was preceded by high caspase activity. In summary, Egr-1 suppressed transformation and counteracted apoptosis by the coordinated activation of TGFβ1, FN, p21 and FAK, leading to enhanced cell attachment and reduced caspase activity. In the doubly expressing cell line, the survival effect of Egr-1 was dominant over the apoptotic effect of p53.

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Abbreviations

FACS:

fluorescence-activated cell sorting

FAK:

focal adhesion kinase

FN:

fibronectin

JNK:

jun kinase

PBS:

phosphate buffered saline

PAI-1:

plasminogen activator inhibitor-1

TGFβ:

transforming growth factor β

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Acknowledgements

We thank our colleagues at the Burnham Institute, S Frisch, A Marti, JC Reed, I Tamm and X Zhang, for gifts of antibodies, for advice and for critical comments on the manuscript. We are indebted to B Vogelstein and J Trill for plasmids, and to JT Parsons for antibodies to PYK-2. We are grateful for support from the Public Health Services, grant CA 67888 (ED Adamson), CA 63783 and CA76173, (D Mercola) from the National Cancer Institute.

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Author notes

  1. Ian de Belle and Ruo-Pan Huang: I de Belle and R-P Huang made equal contributions to this work

Authors and Affiliations

  1. La Jolla Cancer Research Center, The Burnham Institute, 10901, N Torrey Pines Road, La Jolla, CA 92037, California, USA

    Ian de Belle & Eileen D Adamson

  2. Molecular Medicine, Northwest Hospital, 120 Northgate Plaza, Suite 230, Seattle, WA 98125, Washington, USA

    Ruo-Pan Huang & Yan Fan

  3. Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121, California, USA

    Chaoting Liu & Dan Mercola

  4. Center for Molecular Genetics, University of California at San Diego, CA 92093, California, USA

    Chaoting Liu & Dan Mercola

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de Belle, I., Huang, RP., Fan, Y. et al. p53 and Egr-1 additively suppress transformed growth in HT1080 cells but Egr-1 counteracts p53-dependent apoptosis. Oncogene 18, 3633–3642 (1999). https://doi.org/10.1038/sj.onc.1202696

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