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Apaf-1 and caspase-9 do not act as tumor suppressors in myc-induced lymphomagenesis or mouse embryo fibroblast transformation.

Scott CL, Schuler M, Marsden VS, Egle A, Pellegrini M, Nesic D, Gerondakis S, Nutt SL, Green DR, Strasser A - J. Cell Biol. (2004)

Bottom Line: Based on experiments with cultured fibroblasts, the apoptosis regulators caspase-9 and Apaf-1 are hypothesized to function as tumor suppressors.Surprisingly, no differences were seen in rate, incidence, or severity of lymphoma with loss of Apaf-1 or caspase-9, and Apaf-1 was not a critical determinant of anticancer drug sensitivity of c-myc-induced lymphomas.Thus, Apaf-1 and caspase-9 do not suppress c-myc-induced lymphomagenesis and embryo fibroblast transformation.

View Article: PubMed Central - PubMed

Affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.

ABSTRACT
Based on experiments with cultured fibroblasts, the apoptosis regulators caspase-9 and Apaf-1 are hypothesized to function as tumor suppressors. To investigate their in vivo role in lymphomagenesis, an IgH enhancer-driven c-myc transgene was crossed onto Apaf-1(-/-) and caspase-9(-/-) mice. Due to perinatal lethality, Emu-myc transgenic Apaf-1(-/-) or caspase-9(-/-) fetal liver cells were used to reconstitute lethally irradiated recipient mice. Surprisingly, no differences were seen in rate, incidence, or severity of lymphoma with loss of Apaf-1 or caspase-9, and Apaf-1 was not a critical determinant of anticancer drug sensitivity of c-myc-induced lymphomas. Moreover, loss of Apaf-1 did not promote oncogene-induced transformation of mouse embryo fibroblasts. Thus, Apaf-1 and caspase-9 do not suppress c-myc-induced lymphomagenesis and embryo fibroblast transformation.

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Sensitivity of lymphoma-derived cell lines to apoptotic stimuli. Stable cell lines were derived from fresh lymphomas and sorted by flow cytometry using a modified FACSII® or FACStar. For cell death analysis, viable cells (negative for PI) were cultured in DME at a concentration of 0.2–0.5 × 106 cells/ml in 96-well flat bottom microtiter plates. Medium alone (A), 100 nM dexamethasone (B), 10 μg/ml etoposide (C,) and 10 Gy γ-irradiation (D). Eμ-myc (open square), Eμ-myc/Apaf-1+/− (triangle, hashed line), Eμ-myc/Apaf-1−/− (closed circle). Two to three independently derived lines per genotype.
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fig4: Sensitivity of lymphoma-derived cell lines to apoptotic stimuli. Stable cell lines were derived from fresh lymphomas and sorted by flow cytometry using a modified FACSII® or FACStar. For cell death analysis, viable cells (negative for PI) were cultured in DME at a concentration of 0.2–0.5 × 106 cells/ml in 96-well flat bottom microtiter plates. Medium alone (A), 100 nM dexamethasone (B), 10 μg/ml etoposide (C,) and 10 Gy γ-irradiation (D). Eμ-myc (open square), Eμ-myc/Apaf-1+/− (triangle, hashed line), Eμ-myc/Apaf-1−/− (closed circle). Two to three independently derived lines per genotype.

Mentions: No loss of heterozygosity, determined by PCR as loss of the wild-type allele (Fig. 1), was observed for Apaf-1 in either lymphomas (0/19) or cell lines derived from these tumors (0/6), indicating that loss of Apaf-1 is not selected for, nor is haplo-insufficiency limiting in, c-myc–induced lymphoma development in vivo (Fig. 3) or for growth of lymphoma cell lines in culture (Fig. 4).


Apaf-1 and caspase-9 do not act as tumor suppressors in myc-induced lymphomagenesis or mouse embryo fibroblast transformation.

Scott CL, Schuler M, Marsden VS, Egle A, Pellegrini M, Nesic D, Gerondakis S, Nutt SL, Green DR, Strasser A - J. Cell Biol. (2004)

Sensitivity of lymphoma-derived cell lines to apoptotic stimuli. Stable cell lines were derived from fresh lymphomas and sorted by flow cytometry using a modified FACSII® or FACStar. For cell death analysis, viable cells (negative for PI) were cultured in DME at a concentration of 0.2–0.5 × 106 cells/ml in 96-well flat bottom microtiter plates. Medium alone (A), 100 nM dexamethasone (B), 10 μg/ml etoposide (C,) and 10 Gy γ-irradiation (D). Eμ-myc (open square), Eμ-myc/Apaf-1+/− (triangle, hashed line), Eμ-myc/Apaf-1−/− (closed circle). Two to three independently derived lines per genotype.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171953&req=5

fig4: Sensitivity of lymphoma-derived cell lines to apoptotic stimuli. Stable cell lines were derived from fresh lymphomas and sorted by flow cytometry using a modified FACSII® or FACStar. For cell death analysis, viable cells (negative for PI) were cultured in DME at a concentration of 0.2–0.5 × 106 cells/ml in 96-well flat bottom microtiter plates. Medium alone (A), 100 nM dexamethasone (B), 10 μg/ml etoposide (C,) and 10 Gy γ-irradiation (D). Eμ-myc (open square), Eμ-myc/Apaf-1+/− (triangle, hashed line), Eμ-myc/Apaf-1−/− (closed circle). Two to three independently derived lines per genotype.
Mentions: No loss of heterozygosity, determined by PCR as loss of the wild-type allele (Fig. 1), was observed for Apaf-1 in either lymphomas (0/19) or cell lines derived from these tumors (0/6), indicating that loss of Apaf-1 is not selected for, nor is haplo-insufficiency limiting in, c-myc–induced lymphoma development in vivo (Fig. 3) or for growth of lymphoma cell lines in culture (Fig. 4).

Bottom Line: Based on experiments with cultured fibroblasts, the apoptosis regulators caspase-9 and Apaf-1 are hypothesized to function as tumor suppressors.Surprisingly, no differences were seen in rate, incidence, or severity of lymphoma with loss of Apaf-1 or caspase-9, and Apaf-1 was not a critical determinant of anticancer drug sensitivity of c-myc-induced lymphomas.Thus, Apaf-1 and caspase-9 do not suppress c-myc-induced lymphomagenesis and embryo fibroblast transformation.

View Article: PubMed Central - PubMed

Affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.

ABSTRACT
Based on experiments with cultured fibroblasts, the apoptosis regulators caspase-9 and Apaf-1 are hypothesized to function as tumor suppressors. To investigate their in vivo role in lymphomagenesis, an IgH enhancer-driven c-myc transgene was crossed onto Apaf-1(-/-) and caspase-9(-/-) mice. Due to perinatal lethality, Emu-myc transgenic Apaf-1(-/-) or caspase-9(-/-) fetal liver cells were used to reconstitute lethally irradiated recipient mice. Surprisingly, no differences were seen in rate, incidence, or severity of lymphoma with loss of Apaf-1 or caspase-9, and Apaf-1 was not a critical determinant of anticancer drug sensitivity of c-myc-induced lymphomas. Moreover, loss of Apaf-1 did not promote oncogene-induced transformation of mouse embryo fibroblasts. Thus, Apaf-1 and caspase-9 do not suppress c-myc-induced lymphomagenesis and embryo fibroblast transformation.

Show MeSH
Related in: MedlinePlus