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Published on: January 7, 2019
Oncogenes do not Fully Override Cell-intrinsic Traits: Pronounced Impact of the Cellular Programme
Józefa Węsierska-Gądek1, Eva Walzi1, Iva Dolečkova1
1Cell Cycle Regulation Group, Div. Institute of Cancer Research, Dept. of Medicine I, Medical University of Vienna, Borschkegasse 8 a, Vienna, A-1090 Austria.
Abstract:
Overexpression of p53 tumor suppressor protein in malignant cells induces cell cycle arrest, or alternatively, apoptosis thereby indicating that additional factors may contribute to the p53-mediated outcome. Comparison of the experimental protocols revealed that the construct encoding wild-type (wt) p53 was expressed in cells of different origin. Therefore, we decided to determine whether the intrinsic cellular program of primary cells of the same genetic background could have any effect on the oncogenic potential of mutated c-Ha-RAS and TP53. Primary rat cells (RECs) isolated from rat embryos of different age: at 13.5 gd (y) and 15.5 gd (o), were used for transfection. Immortalized rat cell clones overexpressing temperature-sensitive (ts) p53(135val) mutant and transformed cell clones after co-transfection with oncogenic c-Ha-Ras, were generated. The ts p53(135Val) mutant, switching between wt and mutant conformation, offers the possibility to study the role of p53 in cell cycle control in a model of malignant transformation in cells with the same genetic background. Surprisingly, the kinetics of cell proliferation at non-permissive temperature and that of cell cycle arrest at 32°C strongly differed between cell clones established from yRECs and oRECs. Furthermore, the kinetics of the re-enter of G1-arrested cells in the active cell cycle strongly differed between distinct cell clones. Finally, the susceptibility of immortalized and transformed cells to the pharmacological inhibitors of cyclin-dependent kinases (CDKs) considerably differed. Our results clearly show that overexpression of genes such as mutated TP53 and oncogenic c-Ha-RAS is not able to fully override the intrinsic cellular programme.
Insights
The intrinsic cellular program influences cancer development, even with mutations in TP53 and c-Ha-RAS. Cell cycle control and proliferation kinetics differ based on embryo age, affecting responses to genetic alterations and drug treatments.
Area of Science:
- Cell Biology
- Molecular Oncology
- Genetics
Background:
- Overexpression of the p53 tumor suppressor protein can induce cell cycle arrest or apoptosis in malignant cells.
- The outcome of p53-mediated effects may involve additional contributing factors.
- Previous studies noted variations in p53 wild-type (wt) expression across different cell types.
Purpose of the Study:
- To investigate the influence of the intrinsic cellular program in primary cells on the oncogenic potential of mutated c-Ha-RAS and TP53.
- To determine if embryonic age affects cellular responses to oncogenic mutations.
- To analyze the role of p53 in cell cycle control during malignant transformation.
Main Methods:
- Primary rat embryo cells (RECs) from different gestational ages (13.5 days - yRECs, 15.5 days - oRECs) were transfected.
- Immortalized rat cell clones overexpressing a temperature-sensitive (ts) p53(135Val) mutant and transformed clones with oncogenic c-Ha-Ras were generated.
- Cell proliferation, cell cycle arrest/re-entry kinetics, and susceptibility to cyclin-dependent kinase (CDK) inhibitors were assessed.
Main Results:
- Significant differences in cell proliferation kinetics at non-permissive temperatures and cell cycle arrest at 32°C were observed between clones derived from yRECs and oRECs.
- The kinetics of G1-arrested cells re-entering the cell cycle varied considerably among distinct cell clones.
- Immortalized and transformed cells exhibited differing sensitivities to pharmacological CDK inhibitors.
Conclusions:
- The intrinsic cellular program of primary cells plays a significant role in modulating the effects of oncogenic mutations.
- Mutations in TP53 and c-Ha-RAS cannot completely override the inherent cellular regulatory mechanisms.
- Embryonic age and the resulting intrinsic cellular program influence cellular responses to oncogenic stress and therapeutic interventions.
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