EGR-1 was cloned in several laboratories nearly simultaneously (1-6) as the result of efforts to define new factors responsible for growth regulation. However, direct evidence for growth promoting role by EGR-1 remained elusive. Our studies with PDGF-B transformed NIH-3T3 and human HT1080 fibrosarcoma cells (7-8) and studies of others with v-raf transformed NIH-3T3 cells (9) have revealed that EGR-1 actually exerts a strong growth and transformation suppressor activity including decreased tumorigenicity (7-8). Conversely, expression of antisense EGR-1 RNA in NIH-3T3 cells (7) and human prostate carcinoma PC3 cells (8) leads to reduced endogenous EGR-1 and a much more transformed phenotype indicating that endogenous EGR-1 is growth suppressive. Numerous studies show that EGR-1 is within a small region of 5q31.1 that is consistently deleted in AML and other solid tumor malignancies (11-12, 41-43). Moreover, we find that EGR-1 is not expressed and/or uninducible in a variety of established and primary human tumor lines. Studies summarized here provide a mechanistic basis for the inhibition of transformation by EGR-1 by showing that EGR-1 activates a minimal human TGF-beta 1 promoter and causes secretion of active TGF- beta 1. It is hypothesized that suppression of transformation by EGR-1 is dependent on direct stimulation of the TGF- beta 1 gene leading to secretion of TGF- beta 1 which is growth suppressive for certain tumor cell lines. We will test whether the EGR-1/TGF-beta 1 is a general growth regulatory mechanism (AIM 1), whether EGR-1 is a physiologically relevant activator of TGF- beta 1 (AIM 2), whether induction of TGF-beta 1 by EGR-1 is due to direct TGF- beta 1 promoter binding by EGR-1 (AIM 3), whether restoration of TGF- beta 1 sensitivity in human colon and breast carcinomas also restores suppression by EGR-1 and whether TGF- beta 1 is essential for suppression of growth by EGR-1 (AIM 4), and whether loss of heterozygosity, other deletion or aberrant trans- regulation occur in the tumor lines which exhibit aberrant expression and regulation (AIM 5). These studies will elaborate a new mechanism of action for the transcription factor EGR-1 and will evaluate a new regulatory pathway controlling the expression of TGF- beta 1. Inactivation of the signal transduction pathway of TGF- beta 1 has been implicated as common in several major human malignancies and restoration TGF- beta 1 sensitivity suppresses transformation. Loss or defects in EGR-1 is a potential means of disrupting growth control by TGF- beta 1 and this is the tested here (AIM 2).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076173-03
Application #
6124495
Study Section
Pathology B Study Section (PTHB)
Program Officer
Freeman, Colette S
Project Start
1997-12-10
Project End
2002-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
3
Fiscal Year
2000
Total Cost
$309,514
Indirect Cost
Name
Sidney Kimmel Cancer Center
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92121
Pio, Rebecca; Jia, Zhenyu; Baron, Veronique T et al. (2013) Early growth response 3 (Egr3) is highly over-expressed in non-relapsing prostate cancer but not in relapsing prostate cancer. PLoS One 8:e54096
Yu, Jianxiu; Zhang, Sharon S; Saito, Kan et al. (2009) PTEN regulation by Akt-EGR1-ARF-PTEN axis. EMBO J 28:21-33
Yu, J; Baron, V; Mercola, D et al. (2007) A network of p73, p53 and Egr1 is required for efficient apoptosis in tumor cells. Cell Death Differ 14:436-46
Krones-Herzig, Anja; Mittal, Shalu; Yule, Kelly et al. (2005) Early growth response 1 acts as a tumor suppressor in vivo and in vitro via regulation of p53. Cancer Res 65:5133-43
Baron, Veronique; De Gregorio, Giorgia; Krones-Herzig, Anja et al. (2003) Inhibition of Egr-1 expression reverses transformation of prostate cancer cells in vitro and in vivo. Oncogene 22:4194-204
Glinsky, Gennadi V; Krones-Herzig, Anja; Glinskii, Anna B (2003) Malignancy-associated regions of transcriptional activation: gene expression profiling identifies common chromosomal regions of a recurrent transcriptional activation in human prostate, breast, ovarian, and colon cancers. Neoplasia 5:218-28
Krones-Herzig, Anja; Adamson, Eileen; Mercola, Dan (2003) Early growth response 1 protein, an upstream gatekeeper of the p53 tumor suppressor, controls replicative senescence. Proc Natl Acad Sci U S A 100:3233-8
Baron, Veronique; Duss, Stephan; Rhim, Johng et al. (2003) Antisense to the early growth response-1 gene (Egr-1) inhibits prostate tumor development in TRAMP mice. Ann N Y Acad Sci 1002:197-216
Virolle, Thierry; Krones-Herzig, Anja; Baron, Veronique et al. (2003) Egr1 promotes growth and survival of prostate cancer cells. Identification of novel Egr1 target genes. J Biol Chem 278:11802-10
Cripe, L D; Gelfanov, V M; Smith, E A et al. (2002) Role for c-jun N-terminal kinase in treatment-refractory acute myeloid leukemia (AML): signaling to multidrug-efflux and hyperproliferation. Leukemia 16:799-812

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