Oncogenic conversion alters the transcriptional properties of ets.
The vEts oncoprotein and its progenitor cEts1(p68) belong to a growing family of transcription factors that are related by the conserved ets domain. We show here that the ets domain and adjacent COOH-terminal amino acids are required for DNA binding by cEts1(p68). vEts differs from cEts1(p68) in both the COOH-terminal sequence and an amino acid substitution in the ets domain. The change in the COOH-terminal sequence markedly decreases its affinity for specific DNA, and the ets domain mutation further diminishes binding. vEts does not trans-activate through the ets (PEA3) motif in vivo. Surprisingly, vEts still efficiently trans-activates the promoters of two genes, stromelysin and collagenase, that are found to be overexpressed in transformed cells. The AP1 motifs of both promoters are required for efficient activation. vEts does not bind to the AP1 motif, even in the presence of cJun and cFos. The DNA-binding domain of Ets1 is required for activation through the AP1 element. Activation is inhibited by the expression of the glucocorticoid and retinoic acid receptors, suggesting that activation by Ets does not involve reversal of negative regulators of AP1. We suggest that activation is by an indirect mechanism involving activation of endogenous genes. Our results show that vEts differs from its progenitor cEts1(p68) in its trans-activating properties. The findings suggest that activation of the Jun and Fos oncoprotein pathway is important for transformation by Ets.
Wasylyk
C
C
Centre National de la Recherche Scientifique-Laboratoire de Génétique Moléculaire des Eucaryotes/Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine, Strasbourg, France.
Wasylyk
B
B
D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D017364:Collagenases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000235:genetics; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011401:Promoter Regions, Genetic; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000502:physiology; D018168:Receptors, Retinoic Acid; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C494041:ETS1 protein, human; D009838:Oligodeoxyribonucleotides; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D016755:Proto-Oncogene Proteins c-jun; D011965:Receptors, Glucocorticoid; D018168:Receptors, Retinoic Acid; D015682:Retroviridae Proteins, Oncogenic; D014157:Transcription Factors; C050379:oncogene proteins v-ets; D017364:Collagenases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3