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Wild-type p53-triggered apoptosis is inhibited by bcl-2 in a v-myc-induced T-cell lymphoma line
Abstract:
Using a temperature sensitive p53 construct (ts p53), we have earlier shown that expression of wild-type (wt) p53 triggers apoptosis in a v-myc-induced T-cell lymphoma line that lacks endogenous p53, and in a Burkitt lymphoma line that carries mutant p53. We have suggested that apoptosis is elicited by the contradictory signals emanating from the constitutively activated myc gene and the growth arresting signal of wt p53 (Ramqvist et al., 1993; Wang et al., 1993). Work in other laboratories has shown that constitutive c-myc expression can induce apoptosis when cell proliferation is inhibited due to the lack of growth stimulating factors. Expression of bcl-2 could inhibit apoptosis. In order to test whether p53-induced apoptosis can be prevented by bcl-2, we have introduced a retrovirally driven bcl-2 construct into our v-myc-induced murine T-cell lymphoma line, previously transfected with ts p53. About 90% of the parental ts p53 transfected cells died of apoptosis within 3 days after induction of wt p53 expression at 32 degrees C. Two clones of ts p53/bcl-2 double transfectants that expressed high levels of bcl-2 from the introduced construct were completely protected from apoptosis, following transfer of the cells to 32 degrees C. One clone that expressed the exogenous bcl-2 only at a low level was partially protected from wt p53-induced apoptosis. Clones of the parental ts p53 carrying cells transfected with the puromycin resistance gene vector, without the bcl-2 gene underwent 90% apoptosis. These results suggest that bcl-2 may prevent apoptosis in cells simultaneously exposed to the proliferation-stimulating effect of activated myc and the growth arresting signal of wt p53.
Insights
Bcl-2 (B-cell lymphoma 2) protein can prevent apoptosis, programmed cell death, in T-cell lymphoma cells. This occurs even when cells receive contradictory signals from wild-type p53 and activated myc, suggesting a role for bcl-2 in cancer therapy.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Wild-type (wt) p53 expression can induce apoptosis in cancer cells lacking functional p53 or carrying mutant p53.
- Constitutive c-myc expression can also trigger apoptosis when cell proliferation is limited.
- Bcl-2 (B-cell lymphoma 2) is known to inhibit apoptosis.
Purpose of the Study:
- To investigate whether bcl-2 can prevent p53-induced apoptosis in a specific cancer cell model.
- To determine if bcl-2 interferes with apoptosis triggered by the combined signals of wt p53 and activated myc.
Main Methods:
- Introduction of a retrovirally driven bcl-2 construct into a v-myc-induced murine T-cell lymphoma line previously transfected with temperature-sensitive p53 (ts p53).
- Induction of wt p53 expression by shifting cells to 32 degrees C.
- Assessment of apoptosis rates in ts p53/bcl-2 double transfectants and control cells.
Main Results:
- Parental ts p53 transfected cells showed approximately 90% apoptosis within 3 days of wt p53 induction.
- Two clones with high bcl-2 expression were completely protected from p53-induced apoptosis.
- One clone with low bcl-2 expression showed partial protection, while control cells without bcl-2 underwent 90% apoptosis.
Conclusions:
- Bcl-2 effectively prevents apoptosis induced by wt p53 in the presence of activated myc.
- These findings suggest that bcl-2 plays a critical role in overcoming apoptosis triggered by conflicting cellular signals.
- Bcl-2's anti-apoptotic function may be a target for therapeutic intervention in cancers with deregulated p53 and myc pathways.