Transcriptional Down-regulation of Epidermal Growth Factor Receptors by Nerve Growth Factor Treatment of PC12 Cells*
- From the Section on Growth Factors, NICHD and the ¶Laboratory of Molecular Biology, Division of Basic Sciences, NCI, National Institutes of Health, Bethesda, Maryland 20892
Abstract
Treatment of PC12 cells with nerve growth factor leads to a decrease in the number of epidermal growth factor receptors on the cell membrane. The mRNA for the epidermal growth factor receptor decreases in a comparable fashion. This decrease appears due to a decrease in the transcription of the epidermal growth factor receptor gene because first, there is no difference in the stability of the epidermal growth factor receptor mRNA, second, newly transcribed epidermal growth factor receptor mRNA is decreased in nerve growth factor-differentiated cells, and third, constructs containing the promoter region of the epidermal growth factor receptor gene are transcribed much less readily in nerve growth factor-differentiated cells than in untreated cells. The decreases in mRNA are not seen in the p140trk-deficient variant PC12nnr5 cells nor in cells containing either dominant-negative Ras or dominant-negative Src. Treatment with nerve growth factor also increases the cellular content of GCF2, a putative transcription factor inhibitory for the transcription of the epidermal growth factor receptor gene. The increase in GCF2, like the decrease in the epidermal growth factor receptor mRNA, is not seen in PC12nnr5 cells nor in cells expressing either dominant-negative Ras or dominant-negative Src. The results suggest that nerve growth factor-induced down-regulation of the epidermal growth factor receptor is under transcriptional control, is p140trk-, Ras-, and Src-dependent, and may involve transcriptional repression by GCF2.
Footnotes
-
↵* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) U69609.
-
↵‡ Present address: Div. of Pathology, National Inst. of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158, Japan.
-
↵§ Present address: Dept. of Pharmacology, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91010, Israel.
-
↵‖ To whom correspondence should be addressed: Bldg. 49, Rm. 5A64, NIH, Bethesda, MD 20892. Tel.: 301-496-4751; Fax: 301-402-2079; E-mail: gordong{at}helix.nih.gov.
-
↵1 The abbreviations used are: NGF, nerve growth factor; EGF, epidermal growth factor; EGFR, EGF receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MAP, mitogen-activated protein; GST, glutathione S-transferase; kb, kilobase(s); RT, reverse transcription; PCR, polymerase chain reaction; bp, base pair.
-
↵2 A. L. Reed, H. Yamazaki, J. Kaufman, Y. Rubinstein, and A. C. Johnson, submitted for publication.
-
- Received September 5, 1997.
- Revision received January 2, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
