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 gliomas

Citation
A. Calogero et al., 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 gliomas, CLIN CANC R, 7(9), 2001, pp. 2788-2796
Citations number
43
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology
Journal title
CLINICAL CANCER RESEARCH
ISSN journal
1078-0432 → ACNP
Volume
7
Issue
9
Year of publication
2001
Pages
2788 - 2796
Database
ISI
SICI code
1078-0432(200109)7:9<2788:TEGRGE>2.0.ZU;2-X
Abstract
Purpose: EGR-1 is an immediate early gene with diverse functions that inclu de the suppression of growth. EGR-1 is down-regulated many cancer cell type s, suggesting a tumor suppressor role, and may critically involve the p53 p athway. 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 mali gnancy were investigated for Egr-1 mRNA and the protein expression, frequen cy, and spectrum of p53 gene mutations, mdm2 gene amplification, and p16/IN K4a/ARF allele loss. Results: The amplification of Mdm2 and the deletion of the p16/INK4a gene w as found in 3 and 5 cases, respectively, whereas mutations of p53, includin g two novel mutations, were observed in 10 other cases. The three types of changes occurred strictly mutually exclusively, emphasizing that these gene s operate in a common pathway critical to glioma progression. EGR-1 mRNA wa s significantly down-regulated in astrocytomas (14.7 +/- 5.1 %) and in glio blastomas (33.6 +/- 10.0%) versus normal brain. Overall, EGR-1 mRNA was str ongly suppressed (average, 15.2 +/- 13.9%) in 27 of 31 cases (87%), indepen dent of changes in p16/INK4a/ARF and Mdm2; whereas 4 of 31 cases with resid ual EGR-1 expression as well as the highest EGR-1 variance segregated with p53 mutations. Immunohistochemical analyses confirmed the suppression of EG R-1 protein. Conclusions: These results indicate that EGR-1 is commonly suppressed in gl iomas independent of p16/INK4a/ ARF and Mdm2 and that suppression is less c rucial in tumors bearing p.53 mutations, and these results implicate an EGR -1 growth regulatory mechanism as a target of inactivation during tumor pro gression.