P53 and egr-1 additively suppress transformed growth in ht1080 cells but egr-1 counteracts p53-dependent apoptosis

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. Access through your institution Buy or subscribe

This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 50 print issues and online access

$259.00 per year only $5.18 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are

calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS

PPM1D ACTIVITY PROMOTES CELLULAR TRANSFORMATION BY PREVENTING SENESCENCE AND CELL DEATH Article Open access 05 September 2024 NEW DUAL INDUCIBLE CELLULAR MODEL TO INVESTIGATE TEMPORAL

CONTROL OF ONCOGENIC COOPERATING GENES Article Open access 05 September 2024 ACQUISITION OF ANEUPLOIDY DRIVES MUTANT P53-ASSOCIATED GAIN-OF-FUNCTION PHENOTYPES Article Open access 31 August

2021 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 REFERENCES * Ahmed MM, Venkatasubbarao K, Fruitwala SM, Muthukkumar S, Wood Jr DP, Sells SF, Mohiuddin M and Rangnekar VM. . 1996

_J. Biol. Chem._ 271: 29231–29237. * Ahmed MM, Sells SF, Venkatasubbarao K, Fruitwala SM, Muthukkumar S, Harp C, Mohiuddin M and Rangnekar VM. . 1997 _J. Biol. Chem._ 272: 33056–33061. *

Akagi M, Yasui W, Akama Y, Yokozaki H, Tahara H, Haruma K, Kajiyama G and Tahara E. . 1996 _Jap. J. Cancer Res._ 87: 377–384. * Akamatsu H, Ichihara-Tanaka K, Ozono K, Kamiike W, Matsuda H

and Sekiguchi K. . 1996 _Cancer Res._ 56: 4541–4546. * Baker SJ, Markowitz S, Fearon ER, Willson JK and Vogelstein B. . 1990 _Science_ 249: 912–915. * Chang YC, Lee YS, Tejima T, Tanaka K,

Omura S, Heintz NH, Mitsui Y and Magae J. . 1998 _Cell Growth Diff._ 9: 79–84. * Del Sal G, Murphy M, Ruaro E, Lazarevic D, Levine AJ and Schneider C. . 1996 _Oncogene_ 12: 177–185. *

Deveraux QL, Takahashi R, Salvesen GS and Reed JC. . 1997 _Nature_ 388: 300–304. * Diller L, Kassel J, Nelson CE, Gryka MA, Litwak G, Gebhardt M, Bressac B, Ozturk M, Baker SJ and Vogelstein

B and Friend SH. . 1990 _Mol. Cell. Biol._ 10: 5772–5781. * Dinkel A, Aicher WK, Haas C, Zipfel PF, Peter HH and Eibel H. . 1997 _J. Immunol._ 159: 2678–2684. * El-Deiry WS, Tokino T,

Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW and Vogelstein B. . 1993 _Cell_ 75: 817–825. * El-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman C,

Jackman J, Pietenpol JA and Burrell M, Hill DE, Wang Y, Wiman KG, Mercer WE, Kastan MB, Kohn KW, Elledge SJ, Kinzler KW and Vogelstein B. . 1994 _Cancer Res._ 54: 1169–1174. * Frisch SM. .

1994 _J. Cell. Biol._ 127: 1085–1096. * Frisch SM and Francis H. . 1994 _J. Cell. Biol._ 124: 619–626. * Frisch SM. . 1996 _Mutation Research_ 350: 261–266. * Frisch SM, Vuori K, Ruoslahti E

and Chan-Hui PY. . 1996 _J. Cell. Biol._ 134: 793–799. * Fuchs EJ, McKenna KA and Bedi A. . 1997 _Cancer Res._ 57: 2550–2554. * Gervais JL, Seth P and Zhang H. . 1998 _J. Biol. Chem._ 273:

19207–19212. * Globus RK, Doty SB, Lull JC, Holmuhamedov E, Humphries HJ and Damsky CH. . 1998 _J. Cell Sci._ 111: 1385–1393. * Hallahan DE, Dunphy E, Virudachalam S, Sukhatme VP, Kufe DW

and Weichselbaum RR. . 1995 _J. Biol. Chem._ 270: 30303–30309. * Hibi M, Lin A, Smeal T, Minden A and Karin M. . 1993 _Genes Dev._ 7: 2135–2148. * Huang R-P, Darland T, Okamura D, Mercola D

and Adamson ED. . 1994a _Oncogene_ 9: 1367–1377. * Huang R-P, Ngo L, Okamura D, Tucker M and Adamson ED. . 1994b _J. Cell. Biochem._ 56: 469–479. * Huang RP and Adamson ED. . 1995 _Oncogene_

10: 467–475. * Huang R-P, Liu C-T, Fan Y, Mercola DA and Adamson ED. . 1995 _Cancer Res._ 55: 5054–5062. * Huang R-P, Wu J-X, Fan Y and Adamson ED. . 1996 _J. Cell Biol._ 133: 211–220. *

Huang R-P, Fan Y, de Belle I, Niemeyer C, Gottardis MM, Mercola D and Adamson ED. . 1997 _Int. J. Cancer_ 72: 102–109. * Huang R-P, Fan Y, Ni Z-Y, Matheny W and Adamson ED. . 1998a _Cell

Death and Diff._ 5: 96–106. * Huang R-P, Fan Y, Peng A, Reed JC, Adamson ED and Boynton AL. . 1998b _Int J. Cancer_ 77: 880–886. * Hungerford JE, Compton MT, Matter ML, Hoffstrom BG and Otey

CA. . 1996 _J. Cell. Biol._ 135: 1383–1390. * Keyse SM. . 1993 _Sem. Cancer Biol._ 4: 119–128. * Kieser A, Seitz T, Adler HS, Coffer P, Kremmer E, Crespo P, Gutkind JS, Henderson DW,

Mushinski JF, Kolch W and Mischak H. . 1996 _Genes Dev._ 10: 1455–1466. * Landesman Y, Bringold F, Milne DD and Meek DW. . 1997 _Cellular Signalling_ 9: 291–298. * Levine AJ, Chang A,

Dittmer D, Notterman DA, Silver A, Thorn K, Welsh D and Wu M. . 1994 _J. Lab Clin. Med._ 123: 817–823. * Levine AJ. . 1997 _Cell_ 88: 323–331. * Liebermann DA, Hoffman B and Steinman RA. .

1995 _Oncogene_ 11: 199–210. * Lin J, Wu X, Chen J, Chang A and Levine AJ. . 1994 _Cold Spring Harb. Symp. Quant. Biol._ 59: 215–223. * Liu C, Adamson E and Mercola D. . 1996 _Proc. Natl.

Acad. Sci. USA_ 93: 11831–11836. * Liu C, Yao J, de Belle I, Huang R-P, Adamson ED and Mercola D. . 1999 _J. Biol. Chem._ 274: 4400–4411. * Madden SL, Galella EA, Zhu JS, Bertelsen AH and

Beaudry GA. . 1997 _Oncogene_ 15: 1079–1085. * Merlo GR, Venesio T, Taverna D, Marte BM, Callahan R and Hynes NE. . 1994 _Oncogene_ 9: 443–453. * Mohiuddin M, Ahmed MM, Venkatasubbarao K,

Fruitwala S, Rangnekar V, Cross P and Weinstein M. . 1997 _Proc. Amer. Ass. Cancer Res._ 38: 427. * Muthukkumar S, Nain P, Sells SF, Maddiwar NG, Jacob RJ and Rangnekar VM. . 1995 _Mol. Cell

Biol._ 15: 6262–6272. * Muthukkumar S, Han SS, Rangnekar VM and Bondada S. . 1997 _J. Biol. Chem._ 272: 27987–27993. * Nair P, Muthukkumar S, Sells SF, Han SS, Sukhatme VP and Rangnekar VM.

. 1997 _J. Biol. Chem._ 272: 20131–20138. * Nguyen HO, Hoffman-Libermann B and Liebermann DA. . 1993 _Cell_ 72: 197–209. * Park DS, Stefanis L, Yan CYI, Farinelli SE and Greene LA. . 1996

_J. Biol. Chem._ 271: 21898–21905. * Park JA, Kim KW, Kim S and Lee SK. . 1998 _Eur. J. Biochem._ 257(1): 242–248. * Perry ME and Levine AJ. . 1993 _Curr. Opin. Genet. Dev._ 3: 50–54. *

Planus E, Barlovatz-Meimon G, Rogers RA, Bonavaud S, Ingber DE and Wang N. . 1997 _J. Cell Sci._ 110: 1091–1098. * Sabbatini P, Lin J, Levine AJ and White E. . 1995 _Genes. Dev._ 9:

2184–2192. * Scott G, Cassidy L and Busacco A. . 1997 _J. Invest. Dermatol._ 108(2): 147–153. * Selvakumaran M, Lin HK, Miyashita T, Wang HG, Krajewski S, Reed JC, Hoffman B and Liebermann

D. . 1994 _Oncogene_ 9: 1791–1798. * Smith ML, Chen IT, Zhan Q, O'Connor PM and Fornace Jr AJ. . 1995 _Oncogene_ 10: 1053–1059. * Sukhatme VP, Cao X, Chang LC, Tsai-Morris C-H,

Stamenkovitch D, Ferreira PCP, Cohen DR, Edwards SA, Shows TB, Curran T, Le Beau MM and Adamson ED. . 1988 _Cell_ 53: 37–43. * Weichselbaum RR, Hallahan D, Fuks Z and Kufe D. . 1994 _Int. J.

Radiat. Oncol. Biol. Phys._ 30: 229–234. * Wen LP, Fahrni JA, Troie S, Guan JL, Orth K and Rosen GD. . 1997 _J. Biol. Chem._ 272: 26056–26061. * Wu L and Levine AJ. . 1997 _Mol. Med._ 3:

441–451. * Xiong WC and Parsons JT. . 1997 _J. Cell. Biol._ 139: 529–539. * Xu LH, Owens LV, Sturge GC, Yang X, Liu ET, Craven RJ and Cance WG. . 1996 _Cell Growth Diff._ 7: 413–418. * Zhang

Z, Vuori K, Reed JC and Ruoslahti E. . 1995 _Proc. Natl. Acad. Sci. USA_ 92: 6161–6165. Download references 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. AUTHOR INFORMATION Author notes * Ian de Belle and Ruo-Pan Huang: I de Belle and R-P Huang made equal contributions to this work AUTHORS AND AFFILIATIONS * 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 * Molecular Medicine, Northwest Hospital, 120

Northgate Plaza, Suite 230, Seattle, WA 98125, Washington, USA Ruo-Pan Huang & Yan Fan * Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121, California, USA Chaoting Liu 

& Dan Mercola * Center for Molecular Genetics, University of California at San Diego, CA 92093, California, USA Chaoting Liu & Dan Mercola Authors * Ian de Belle View author

publications You can also search for this author inPubMed Google Scholar * Ruo-Pan Huang View author publications You can also search for this author inPubMed Google Scholar * Yan Fan View

author publications You can also search for this author inPubMed Google Scholar * Chaoting Liu View author publications You can also search for this author inPubMed Google Scholar * Dan

Mercola View author publications You can also search for this author inPubMed Google Scholar * Eileen D Adamson View author publications You can also search for this author inPubMed Google

Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 03 September 1998 *

Revised: 14 January 1999 * Accepted: 14 January 1999 * Published: 14 July 1999 * Issue Date: 17 June 1999 * DOI: https://doi.org/10.1038/sj.onc.1202696 SHARE THIS ARTICLE Anyone you share

the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer

Nature SharedIt content-sharing initiative KEYWORDS * human fibrosarcoma cells * transfection * stable expression * growth * tumorigenicity * UV-C irradiation