The reciprocal role of Egr-1 and Sp family proteins in regulation of the PTP1B promoter in response to the p210 Bcr-Abl oncoprotein-tyrosine kinase.
Protein-tyrosine phosphatase 1B (PTP1B) is an important regulator of protein-tyrosine kinase-dependent signaling pathways. Changes in expression and activity of PTP1B have been associated with various human diseases; however, the mechanisms by which PTP1B expression is regulated have yet to be characterized. Previously, we have shown that the expression of PTP1B is enhanced by p210 Bcr-Abl and that PTP1B is a specific antagonist of transformation induced by this oncoprotein protein-tyrosine kinase. Here we have characterized the PTP1B promoter and demonstrate that a motif with features of a stress-response element acts as a p210 Bcr-Abl-responsive sequence, termed PRS. We have shown that three C(2)H(2) zinc finger proteins, namely Sp1, Sp3, and Egr-1, bind to PRS. Whereas binding of either Sp1 or Sp3 induced promoter function, Egr-1 repressed Sp3-mediated PTP1B promoter activation. The binding of Egr-1 to PRS is suppressed by p210 Bcr-Abl due to the inhibition of Egr-1 expression, resulting in the enhancement of PTP1B promoter activity. Our data indicate that Egr-1 and Sp family proteins play a reciprocal role in the control of expression from the PTP1B promoter.
Fukada
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Cold Spring Harbor Laboratory, Demerec Bldg., 1 Bungtown Rd., Cold Spring Harbor, NY 11724-2208, USA.
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D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D051766:Early Growth Response Protein 1; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D017874:Immediate-Early Proteins; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D017510:Protein Folding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; D014157:Transcription Factors / Q000502:physiology*; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; C497121:SP3 protein, human; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D051705:Sp3 Transcription Factor; D016044:Fusion Proteins, bcr-abl; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases