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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.

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.

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

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

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

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

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

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