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A Harvey-ras responsive transcription element is also responsive to a tumour-promoter and to serum
J L Imler1, C Schatz, C Wasylyk
1Laboratoire de Génétique Moléculaire des Eucaryotes du CNRS, Unité 184 de Biologie Moléculaire et de Génie Génétique, INSERM, Faculté de Médecine, Strasbourg, France.
Abstract:
The ras oncogenes are implicated in the onset of some human tumours, and in cellular proliferation and terminal differentiation. The ras proteins are plasma membrane bound transducers of signals between the outside of the cell and unknown targets in the cell. Identifying these targets and understanding how they are regulated will have a major impact on our understanding of the molecular basis of transformation. We have already shown that c-Ha-ras and the tumor promoter TPA (12-o-tetradecanoyl phorbol-13-acetate) can activate a transcriptional enhancer. We now report the identification of a short sequence in the polyoma virus (Py) enhancer which mediates Ha-ras activation, and show that this sequence (ras responsive element, RRE) also mediates activation by TPA and serum. This responsive element is a specific binding-site for the mouse transcription factor PEA1 (ref. 4 and below) and for the jun oncogene (ref. 5 and M. Karin, personal communication). These results are in keeping with a role for ras protein in signal transduction from outside the cell to a transcription factor in the nucleus, through protein kinase C. The striking similarity between RRE and DNA sequences present in the promoter regions of a number of transformation-related genes suggests that deregulated activation of RRE is a critical event in transformation.
Insights
Ras oncogenes drive tumor development by activating a specific DNA sequence, the ras-responsive element (RRE). This RRE acts as a crucial link in cellular signaling pathways, impacting cell growth and differentiation.
Area of Science:
- Molecular Biology
- Oncology
- Cellular Signaling
Background:
- Ras oncogenes are crucial in human tumor development, cellular proliferation, and differentiation.
- Ras proteins act as signal transducers from the cell surface to intracellular targets, but these targets remain largely unknown.
- Understanding ras protein regulation is key to deciphering the molecular basis of cell transformation.
Purpose of the Study:
- To identify the targets of ras protein signaling.
- To understand the regulatory mechanisms of ras proteins.
- To investigate the role of ras in activating transcriptional enhancers.
Main Methods:
- Identification of a specific DNA sequence in the polyoma virus enhancer mediating ras activation.
- Demonstration that this sequence, the ras-responsive element (RRE), is activated by ras, TPA, and serum.
- Characterization of RRE as a binding site for transcription factor PEA1 and the jun oncogene.
Main Results:
- A short sequence, the ras-responsive element (RRE), was identified in the polyoma virus enhancer.
- RRE mediates activation by c-Ha-ras, the tumor promoter TPA, and serum.
- RRE serves as a specific binding site for the transcription factor PEA1 and the jun oncogene.
Conclusions:
- Ras protein likely functions in signal transduction, relaying signals from the cell exterior to nuclear transcription factors via protein kinase C.
- The RRE sequence's similarity to promoter regions of transformation-related genes suggests its deregulated activation is critical in cancer development.