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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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Eμ-myc lymphoma onset is not affected by loss of Apaf-1 or caspase-9. Fetal liver cells from Eμ-myc transgenic Apaf-1+/− or Apaf-1−/− or Eμ-myc transgenic caspase-9+/− or caspase-9−/− E14.5 embryos were used to reconstitute lethally irradiated mice. As controls, recipients were reconstituted with fetal liver cells from E14.5 wild-type, Eμ-myc transgenic, or Eμ-myc/Eμ-bcl-2 double transgenic embryos. Mice were killed when noted to be sick and were found to suffer from Eμ-myc lymphoma, with the exception of a small number of poorly reconstituted mice morbid with anemia or infection. (A and B) Kaplan-Meier analysis of tumor-free survival (weeks).
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fig3: Eμ-myc lymphoma onset is not affected by loss of Apaf-1 or caspase-9. Fetal liver cells from Eμ-myc transgenic Apaf-1+/− or Apaf-1−/− or Eμ-myc transgenic caspase-9+/− or caspase-9−/− E14.5 embryos were used to reconstitute lethally irradiated mice. As controls, recipients were reconstituted with fetal liver cells from E14.5 wild-type, Eμ-myc transgenic, or Eμ-myc/Eμ-bcl-2 double transgenic embryos. Mice were killed when noted to be sick and were found to suffer from Eμ-myc lymphoma, with the exception of a small number of poorly reconstituted mice morbid with anemia or infection. (A and B) Kaplan-Meier analysis of tumor-free survival (weeks).

Mentions: Sick animals were killed and autopsied and, with the exception of a small number of poorly reconstituted mice morbid with anemia or infection, were found to suffer from Eμ-myc lymphoma. The rate of lymphoma onset in mice reconstituted with an Eμ-myc /Apaf-1+/+ hemopoietic system was delayed (50% survival: 57 wk; Fig. 3 A) compared with that observed for unmanipulated C57BL/6 Eμ-myc transgenic mice (50% survival: 14 wk; unpublished data). Despite the increase in tumor latency seen in the reconstituted system, which was also reported by Schmitt et al. (2002), and for which the reason is presently unknown, marked acceleration of lymphomagenesis was seen for mice reconstituted with a Eμ-myc/Eμ-bcl-2 hemopoietic system (50% survival: 10 wk, Kaplan-Meier analysis log-rank P = 0.001 for Eμ-myc/Eμ-bcl-2 vs. Eμ-myc; Fig. 3 A). In contrast, loss of one or both alleles of Apaf-1 did not increase the rate or incidence of lymphoma (50% survival: Eμ-myc/Apaf-1+/+ 57 wk; Eμ-myc/Apaf-1+/− 53 wk; and Eμ−myc/Apaf-1−/− 59 wk; Kaplan-Meier analysis log-rank P = 0.9 for Eμ-myc/Apaf-1−/− vs. Eμ-myc/Apaf-1+/+; Fig. 3 A). Similarly, loss of one or both alleles of caspase-9 did not enhance lymphomagenesis (50% tumor-free survival: Eμ-myc/caspase-9+/+ 57 wk; Eμ-myc/caspase-9+/− 52 wk; and Eμ-myc/caspase-9−/− 54 wk; Kaplan-Meier analysis log-rank P = 0.9 for Eμ-myc/caspase-9−/− vs. Eμ-myc/caspase-9+/+; Fig. 3 B). When all causes of mortality were included in the analysis (overall survival), we also found no increase in, or acceleration of, death with loss of Apaf-1 or caspase-9 (Fig. S1, available at http://www.jcb.org/cgi/content/full/jcb.200310041/DC1).


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)

Eμ-myc lymphoma onset is not affected by loss of Apaf-1 or caspase-9. Fetal liver cells from Eμ-myc transgenic Apaf-1+/− or Apaf-1−/− or Eμ-myc transgenic caspase-9+/− or caspase-9−/− E14.5 embryos were used to reconstitute lethally irradiated mice. As controls, recipients were reconstituted with fetal liver cells from E14.5 wild-type, Eμ-myc transgenic, or Eμ-myc/Eμ-bcl-2 double transgenic embryos. Mice were killed when noted to be sick and were found to suffer from Eμ-myc lymphoma, with the exception of a small number of poorly reconstituted mice morbid with anemia or infection. (A and B) Kaplan-Meier analysis of tumor-free survival (weeks).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2171953&req=5

fig3: Eμ-myc lymphoma onset is not affected by loss of Apaf-1 or caspase-9. Fetal liver cells from Eμ-myc transgenic Apaf-1+/− or Apaf-1−/− or Eμ-myc transgenic caspase-9+/− or caspase-9−/− E14.5 embryos were used to reconstitute lethally irradiated mice. As controls, recipients were reconstituted with fetal liver cells from E14.5 wild-type, Eμ-myc transgenic, or Eμ-myc/Eμ-bcl-2 double transgenic embryos. Mice were killed when noted to be sick and were found to suffer from Eμ-myc lymphoma, with the exception of a small number of poorly reconstituted mice morbid with anemia or infection. (A and B) Kaplan-Meier analysis of tumor-free survival (weeks).
Mentions: Sick animals were killed and autopsied and, with the exception of a small number of poorly reconstituted mice morbid with anemia or infection, were found to suffer from Eμ-myc lymphoma. The rate of lymphoma onset in mice reconstituted with an Eμ-myc /Apaf-1+/+ hemopoietic system was delayed (50% survival: 57 wk; Fig. 3 A) compared with that observed for unmanipulated C57BL/6 Eμ-myc transgenic mice (50% survival: 14 wk; unpublished data). Despite the increase in tumor latency seen in the reconstituted system, which was also reported by Schmitt et al. (2002), and for which the reason is presently unknown, marked acceleration of lymphomagenesis was seen for mice reconstituted with a Eμ-myc/Eμ-bcl-2 hemopoietic system (50% survival: 10 wk, Kaplan-Meier analysis log-rank P = 0.001 for Eμ-myc/Eμ-bcl-2 vs. Eμ-myc; Fig. 3 A). In contrast, loss of one or both alleles of Apaf-1 did not increase the rate or incidence of lymphoma (50% survival: Eμ-myc/Apaf-1+/+ 57 wk; Eμ-myc/Apaf-1+/− 53 wk; and Eμ−myc/Apaf-1−/− 59 wk; Kaplan-Meier analysis log-rank P = 0.9 for Eμ-myc/Apaf-1−/− vs. Eμ-myc/Apaf-1+/+; Fig. 3 A). Similarly, loss of one or both alleles of caspase-9 did not enhance lymphomagenesis (50% tumor-free survival: Eμ-myc/caspase-9+/+ 57 wk; Eμ-myc/caspase-9+/− 52 wk; and Eμ-myc/caspase-9−/− 54 wk; Kaplan-Meier analysis log-rank P = 0.9 for Eμ-myc/caspase-9−/− vs. Eμ-myc/caspase-9+/+; Fig. 3 B). When all causes of mortality were included in the analysis (overall survival), we also found no increase in, or acceleration of, death with loss of Apaf-1 or caspase-9 (Fig. S1, available at http://www.jcb.org/cgi/content/full/jcb.200310041/DC1).

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