Suppression of Egr-1 transcription through targeting of the serum response factor by oncogenic H-Ras.
The transcription factor Egr-1 functions as a key regulator in cellular growth, differentiation, and apoptosis. The loss of Egr-1 expression is closely associated with tumor development, although the molecular mechanism behind the suppression of Egr-1 is largely unknown. In this report, we show that growth factor-induced transcriptional activation of Egr-1 gene is downregulated by chronic expression of oncogenic H-Ras in NIH3T3 fibroblasts. Our results demonstrate that phosphoinositide 3-kinase (PI3K) signaling is necessary for oncogenic H-Ras-mediated reduction of Egr-1 gene expression. Aberrant activation of PI3K signaling by oncogenic Ras decreased the level of serum response factor (SRF) protein through the acceleration of proteolysis, which resulted in decreased SRF binding to the serum response element (SRE) sites within the Egr-1 promoter, leading to the suppression of Egr-1 transcription. Inhibition of PI3K signaling restored the downregulation of SRF and Egr-1 expression caused by oncogenic Ras. Our findings suggest a novel signaling mechanism by which prolonged activation of oncogenic H-Ras can trigger the loss of tumor suppressor Egr-1 through the PI3K pathway in NIH3T3 fibroblast model cell lines.
Shin
Soon Young
SY
Division of Molecular & Life Science, College of Science & Technology, Hanyang University, Ansan, Korea.
Bahk
Young Yil
YY
Ko
Jesang
J
Chung
Il-Yup
IY
Lee
Young Seek
YS
Downward
Julian
J
Eibel
Hermann
H
Sharma
Prem M
PM
Olefsky
Jerrold M
JM
Kim
Young-Ho
YH
Lee
Bonghee
B
Lee
Young Han
YH
D016475:3T3 Cells; D000818:Animals; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D015536:Down-Regulation; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D011905:Genes, ras / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D027602:Serum Response Element / Q000235:genetics; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D051766:Early Growth Response Protein 1; D010982:Platelet-Derived Growth Factor; D026362:Serum Response Factor; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D020928:Mitogen-Activated Protein Kinases