This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Calogero, A. Articles by Ragona, G. Search for Related Content PubMed PubMed Citation Articles by Calogero, A. Articles by Ragona, G.

The Early Growth Response Gene EGR-1 Behaves as a Suppressor Gene That Is Down-Regulated Independent of ARF/Mdm2 but not p53 Alterations in Fresh Human Gliomas¹

Department of Molecular Pathology, Istituto di Ricovero e Cura a Carattere Scientifico Neuromed, Pozzilli, 86077 Italy [A. C., A. A., G. D. G., A. P., V. L., F. M. G., R. C., L. F., G. R.]; Departments of Experimental Medicine and Pathology [A. A., A. P., V. L., M. Z., G. G., A. G., L. F., G. R.] and Neurological Sciences [F. M. G., R. C.], University of Rome "La Sapienza," 00161 Rome, Italy; Sidney Kimmel Cancer Center, San Diego, California 92121 [D. M., C. L.]; and The Cancer Center, University of California at San Diego, La Jolla, California 92093 [D. M.]

Purpose: EGR-1 is an immediate early gene with diverse functions that include the suppression of growth. EGR-1 is down-regulated many cancer cell types, suggesting a tumor suppressor role, and may critically involve the p53 pathway. The aim of this work was to measure the expression of EGR-1 and the p16/INK4a/ARF-Mdm2-p53 pathway status in fresh human gliomas.

Experimental Design: Thirty-one human gliomas with different grades of malignancy were investigated for Egr-1 mRNA and the protein expression, frequency, and spectrum of p53 gene mutations, mdm2 gene amplification, and p16/INK4a/ARF allele loss.

Results: The amplification of Mdm2 and the deletion of the p16/INK4a gene was found in 3 and 5 cases, respectively, whereas mutations of p53, including two novel mutations, were observed in 10 other cases. The three types of changes occurred strictly mutually exclusively, emphasizing that these genes operate in a common pathway critical to glioma progression. EGR-1 mRNA was significantly down-regulated in astrocytomas (14.7 ± 5.1%) and in glioblastomas (33.6 ± 10.0%) versus normal brain. Overall, EGR-1 mRNA was strongly suppressed (average, 15.2 ± 13.9%) in 27 of 31 cases (87%), independent of changes in p16/INK4a/ARF and Mdm2; whereas 4 of 31 cases with residual EGR-1 expression as well as the highest EGR-1 variance segregated with p53 mutations. Immunohistochemical analyses confirmed the suppression of EGR-1 protein.

Conclusions: These results indicate that EGR-1 is commonly suppressed in gliomas independent of p16/INK4a/ARF and Mdm2 and that suppression is less crucial in tumors bearing p53 mutations, and these results implicate an EGR-1 growth regulatory mechanism as a target of inactivation during tumor progression.

This article has been cited by other articles:

				A. A. Mourad-Zeidan, V. O. Melnikova, H. Wang, A. Raz, and M. Bar-Eli Expression Profiling of Galectin-3-Depleted Melanoma Cells Reveals its Major Role in Melanoma Cell Plasticity and Vasculogenic Mimicry Am. J. Pathol., December 1, 2008; 173(6): 1839 - 1852. [Abstract] [Full Text] [PDF]

				J. M. Lubieniecka, D. R.H. de Bruijn, L. Su, A. H.A. van Dijk, S. Subramanian, M. van de Rijn, N. Poulin, A. G. van Kessel, and T. O. Nielsen Histone Deacetylase Inhibitors Reverse SS18-SSX-Mediated Polycomb Silencing of the Tumor Suppressor Early Growth Response 1 in Synovial Sarcoma Cancer Res., June 1, 2008; 68(11): 4303 - 4310. [Abstract] [Full Text] [PDF]

				H. Ishikawa, M. Shozu, M. Okada, M. Inukai, B. Zhang, K. Kato, T. Kasai, and M. Inoue Early growth response gene-1 plays a pivotal role in down-regulation of a cohort of genes in uterine leiomyoma J. Mol. Endocrinol., November 1, 2007; 39(5): 333 - 341. [Abstract] [Full Text] [PDF]

				Y. Rong, F. Hu, R. Huang, N. Mackman, J. M. Horowitz, R. L. Jensen, D. L. Durden, E. G. Van Meir, and D. J. Brat Early Growth Response Gene-1 Regulates Hypoxia-Induced Expression of Tissue Factor in Glioblastoma Multiforme through Hypoxia-Inducible Factor-1-Independent Mechanisms. Cancer Res., July 15, 2006; 66(14): 7067 - 7074. [Abstract] [Full Text] [PDF]

				J. Kim, Y. H. Lee, T. K. Kwon, J.-S. Chang, K. C. Chung, and D. S. Min Phospholipase D Prevents Etoposide-Induced Apoptosis by Inhibiting the Expression of Early Growth Response-1 and Phosphatase and Tensin Homologue Deleted on Chromosome 10 Cancer Res., January 15, 2006; 66(2): 784 - 793. [Abstract] [Full Text] [PDF]

				B. J. Stephens, H. Han, V. Gokhale, and D. D. Von Hoff PRL phosphatases as potential molecular targets in cancer Mol. Cancer Ther., November 1, 2005; 4(11): 1653 - 1661. [Abstract] [Full Text] [PDF]

				A. Krones-Herzig, S. Mittal, K. Yule, H. Liang, C. English, R. Urcis, T. Soni, E. D. Adamson, and D. Mercola Early Growth Response 1 Acts as a Tumor Suppressor In vivo and In vitro via Regulation of p53 Cancer Res., June 15, 2005; 65(12): 5133 - 5143. [Abstract] [Full Text] [PDF]

				B. Ferraro, G. Bepler, S. Sharma, A. Cantor, and E. B. Haura EGR1 Predicts PTEN and Survival in Patients With Non-Small-Cell Lung Cancer J. Clin. Oncol., March 20, 2005; 23(9): 1921 - 1926. [Abstract] [Full Text] [PDF]

				J. M. Martinez, S. J. Baek, D. M. Mays, P. K. Tithof, T. E. Eling, and N. J. Walker EGR1 Is a Novel Target for AhR Agonists in Human Lung Epithelial Cells Toxicol. Sci., December 1, 2004; 82(2): 429 - 435. [Abstract] [Full Text] [PDF]

				L. Weisz, A. Zalcenstein, P. Stambolsky, Y. Cohen, N. Goldfinger, M. Oren, and V. Rotter Transactivation of the EGR1 Gene Contributes to Mutant p53 Gain of Function Cancer Res., November 15, 2004; 64(22): 8318 - 8327. [Abstract] [Full Text] [PDF]

				S. J. Baek, J.-S. Kim, J. B. Nixon, R. P. DiAugustine, and T. E. Eling Expression of NAG-1, a Transforming Growth Factor-{beta} Superfamily Member, by Troglitazone Requires the Early Growth Response Gene EGR-1 J. Biol. Chem., February 20, 2004; 279(8): 6883 - 6892. [Abstract] [Full Text] [PDF]

				G. R. Mora, K. R. Olivier, J. C. Cheville, R. F. Mitchell Jr., W. L. Lingle, and D. J. Tindall The Cytoskeleton Differentially Localizes the Early Growth Response Gene-1 Protein in Cancer and Benign Cells of the Prostate Mol. Cancer Res., February 1, 2004; 2(2): 115 - 128. [Abstract] [Full Text] [PDF]

				S.-Z. Yang and S. A. Abdulkadir Early Growth Response Gene 1 Modulates Androgen Receptor Signaling in Prostate Carcinoma Cells J. Biol. Chem., October 10, 2003; 278(41): 39906 - 39911. [Abstract] [Full Text] [PDF]

				F. D. Ragione, V. Cucciolla, V. Criniti, S. Indaco, A. Borriello, and V. Zappia p21Cip1 Gene Expression Is Modulated by Egr1: A NOVEL REGULATORY MECHANISM INVOLVED IN THE RESVERATROL ANTIPROLIFERATIVE EFFECT J. Biol. Chem., June 20, 2003; 278(26): 23360 - 23368. [Abstract] [Full Text] [PDF]

				T. Virolle, A. Krones-Herzig, V. Baron, G. De Gregorio, E. D. Adamson, and D. Mercola Egr1 Promotes Growth and Survival of Prostate Cancer Cells. IDENTIFICATION OF NOVEL Egr1 TARGET GENES J. Biol. Chem., March 28, 2003; 278(14): 11802 - 11810. [Abstract] [Full Text] [PDF]

				A. Krones-Herzig, E. Adamson, and D. Mercola Early growth response 1 protein, an upstream gatekeeper of the p53 tumor suppressor, controls replicative senescence PNAS, March 18, 2003; 100(6): 3233 - 3238. [Abstract] [Full Text] [PDF]

				H. M. Fathallah-Shaykh Darts in the Dark Cure Animal, but Not Human, Brain Tumors Arch Neurol, May 1, 2002; 59(5): 721 - 724. [Full Text] [PDF]