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Oncogenes belonging to the CSF-1 transduction pathway direct p53 tumor suppressor effects to monocytic
R Martinelli1, G Blandino, R Scardigli
1Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, C.R.S., Rome, Italy.
Abstract:
Expression of exogenous wt-p53 in different tumor cell lines can induce growth arrest, apoptosis, or differentiation. Several experimental works have highlighted the relevance of cellular context in the determination of p53-mediated final outcomes. We recently observed that these diverse wt-p53 effects can also be induced by overexpressing wt-p53 in a single cell type-the 32D myeloid progenitors-transformed with different activated oncogenes. Here we show that 32D cells transformed with two different oncogenes, v-src or c-fms [S301,F969], both belonging to the CSF-1 transduction pathway, respond to exogenous wt-p53 expression with the same final outcome-monocytic differentiation. This result is particularly significant since 32D cells do not spontaneously express the CSF-1 receptor, whereas they undergo granulocytic differentiation upon G-CSF stimulation. These data strongly support the idea that wt-p53 suppressing effects result from interactions between p53 activity and the signaling pathways activated in different transformed cells.
Insights
Wild-type p53 (wt-p53) expression induces varied outcomes in tumor cells. In 32D myeloid progenitors, wt-p53 triggers monocytic differentiation, highlighting context-dependent p53 signaling.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Wild-type p53 (wt-p53) expression can induce diverse cellular outcomes like growth arrest, apoptosis, or differentiation.
- The cellular context significantly influences the final outcome of p53-mediated effects.
- Previous studies showed varied wt-p53 effects in different tumor cell lines.
Purpose of the Study:
- To investigate the impact of wt-p53 expression on 32D myeloid progenitor cells transformed with different oncogenes.
- To determine if wt-p53 induces similar outcomes in a single cell type expressing distinct oncogenes.
- To explore the interaction between p53 activity and cellular signaling pathways.
Main Methods:
- Overexpression of exogenous wt-p53 in 32D myeloid progenitor cells.
- Transformation of 32D cells with specific oncogenes (v-src or c-fms).
- Analysis of cellular differentiation and signaling pathway activation.
Main Results:
- 32D cells transformed with v-src or c-fms oncogenes consistently showed monocytic differentiation upon wt-p53 expression.
- This outcome occurred despite 32D cells not typically expressing the CSF-1 receptor or undergoing monocytic differentiation spontaneously.
- The results suggest that wt-p53's tumor-suppressive effects are modulated by activated signaling pathways within the transformed cells.
Conclusions:
- The cellular context, specifically activated oncogenic signaling, dictates the outcome of wt-p53 expression.
- wt-p53 can induce specific differentiation pathways (monocytic) in 32D cells when they are transformed with CSF-1 pathway oncogenes.
- These findings underscore the critical interplay between p53 and cellular signaling in determining cancer cell fate.