Signalling Pathways of Cooperative Oncogenes and Their Effects on the Transcriptional Control of Cell Cycle Genes in Schwann Cell Transformation (Neurofibromatosis).
Abstract
The co-operation between Ras/Raf and SV4O large T (LT) in the transformation of primary rat Schwann cells is a strikingly synergistic process. We have explored the signalling pathways and the molecular mechanisms involved. Either activated Ras or an inducible Raf onco-protein alone, induce a Gi-specific cell cyle arrest. This requires prolonged activation of MAP kinase activity followed by the inhibition of cyclin-dependent kinases (cdk) via induction of the cyclin/cdk inhibitory protein, p21 Cipi. In contrast, when Raf is activated in the presence of LT or dominant-negative (dn)-p53, the cell cycle arrest and p21CIPl induction are specifically abolished and the ability of Raf to increase the specific activity of cyclin-dependent kinases is revealed. Thus Raf-dependent Gi arrest and p2iCIPl induction require p53 function. This indicates that in this scenario p53 plays a key role in signal integration and determines the specificity of the cellular response to the Ras/Raf pathway independent of DNA damage. It appears that this particular feature of p53 together with its involvement in the induction of apoptosis may represent an important element in its role as a tumour suppressor gene in Schwann cells. In addition, we show that super-induction of cyclin A/cdk2 activity is causally involved in the stimulation of Schwann cell proliferation in the absence of mitogens by Raf and LT.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 1996
- Accession Number
- ADB223090
Entities
People
- Hartmut Land