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

Scott, Clare L.; Schüler, Martin; Marsden, Vanessa S.; Egle, Alexander; Pellegrini, Marc; Nešić, Dobrila; Gerondakis, Steve; Nutt, Stephen L.; Green, Douglas R.; Strasser, Andreas

doi:10.1083/jcb.200310041

Cited by 66 publications

(61 citation statements)

References 35 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, nuclear factor-kB, the tumorsuppressor Ink4c, the death protein Apaf1/caspase9, as well as the DNA-modifying enzymes AID and Rag have all been shown to be dispensable for c-Myc-driven tumorigenesis (Scott et al, 2004;Keller et al, 2005;Kotani et al, 2007;Nilsson et al, 2007;Nepal et al, 2008). However, our data show that signals through IL7Ra Y449, such as STAT5, can regulate transformation in this lymphoma model.…”

Section: Il-7ra Y449 Signals Contribute To Lymphomagenesis Lc Osbornementioning

confidence: 58%

Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

et al. 2010

View full text Add to dashboard Cite

Tumor progression is a multiple step process in which, in addition to oncogenic mutation, other supporting factors can contribute to transformation. The role these factors have in cancer is an open question. Using the El-myc model of B-cell transformation, we evaluated the contribution of the cytokine interleukin-7 (IL-7) in supporting lymphomagenesis. We have previously shown that disruption of the Y449xxM motif of the IL-7 receptor alpha (IL-7Ra) in a knock-in mouse model (IL-7Ra 449F ) has minor effects on lymphocyte production, but interferes with the activation of survival effectors. To address the hypothesis that targeted signal ablation would selectively affect lymphocyte transformation, IL-7Ra 449F mice were crossed with two lymphomagenesis models, transgenic (Tg) IL-7 and El-myc mice. We found that the loss of IL-7Ra Y449 signaling prevented Tg IL-7-mediated T-and B-lymphocyte transformation and decreased the development of El-myc-induced B-cell tumors. We showed that the IL-7Ra 449F mutation prevented increased survival of Tg IL-7 CD8 T cells, and decreased viability of bone marrow progenitor B cells, as well as Elmyc-induced proliferation. This study shows that IL-7Ra Y449 is important for lymphocyte transformation, and that unlike deficiencies in pre-B cell receptor signaling, Myc overexpression cannot compensate for the loss of IL-7Ra signals in early B-cell development.

show abstract

Section: Il-7ra Y449 Signals Contribute To Lymphomagenesis Lc Osbornementioning

confidence: 58%

Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

et al. 2010

View full text Add to dashboard Cite

show abstract

“…5 Moreover, cells with permeabilized mitochondria that are incapable of apoptosome-dependent caspase activation ultimately succumb to alternative death mechanisms or permanent growth arrest. 24,25 The integrity of the MOM is guarded by the BCL-2 family of proteins, which make them strategic targets for rational drug development. Especially the group of BH3-only proteins, which are regarded as sensors of cellular stresses, has received much attention in that respect.…”

Section: Discussionmentioning

confidence: 99%

Targeting BCL‐2 family proteins to overcome drug resistance in non‐small cell lung cancer

Wesarg

Hoffarth

Wiewrodt

et al. 2007

Intl Journal of Cancer

Self Cite

102

View full text Add to dashboard Cite

Cytotoxic chemotherapies are standard of care for patients suffering from advanced non-small cell lung cancer (NSCLC). However, objective responses are only achieved in 20% of cases and longterm survival is rarely observed. Clinically applied anticancer drugs exert at least some of their activities by inducing apoptosis. A critical step in apoptotic signal transduction is the permeabilization of the mitochondrial outer membrane (MOM), which is regulated by the BCL-2 family of proteins. Hence, therapeutic targeting of BCL-2 proteins is a promising approach to increase the drug-sensitivity of cancers. To this end we have assessed the impact of conditional expression of the proapoptotic multidomain (BH1-2-3) protein BAK, which directly permeabilizes the MOM, and the BH3-mimetic ABT-737, which acts indirectly by derepressing BH1-2-3 proteins, on apoptosis and drug sensitivity of NSCLC cells. Conditionally expressed BAK sensitized resistant NSCLC cells to drug-induced apoptosis. In contrast, ABT-737 was ineffective in those NSCLC cells expressing high levels of the antiapoptotic MCL-1 protein. Tissue microarray analysis of tumor samples from 84 chemotherapy-na€ ıve NSCLC patients revealed MCL-1 expression in 56% of cases, thus supporting the relevance of this resistance factor in a clinical setting. Enforced expression of the BH3-only protein NOXA, which targets MCL-1, overcame resistance to ABT-737. Moreover, combining conditionally expressed BAK with ABT-737 enhanced apoptosis in NSCLC cells independently of their MCL-1 status. In conclusion, the heterogeneity of apoptosis defects observed in drug-resistant NSCLC demands individually tailored molecular therapies. Targeting the MOM permeabilizer BAK appears to have a broader apoptogenic activity than the BH3-only mimetic ABT-737. ' 2007 Wiley-Liss, Inc.

show abstract

“…9 The expression of BCL-2 proteins correlates with prognosis in some studies of non-small-cell-lung cancer (NSCLC) patients. 10 In contrast, loss of caspase-9 or the adapter Apaf-1 failed to accelerate Myc-induced lymphomagenesis in mice, 11 and inactivating mutations or loss of expression of these factors are rarely observed in human cancers. 12,13 A correlation of nuclear localization of Apaf-1 or caspase expression has been reported to correlate with prognosis in resected NSCLC, 14,15 and studies in cancer cell lines and human leukemias point at a contribution of defective caspase activation to drug resistance by a yet undefined mechanism.…”

mentioning

confidence: 99%

pp32/PHAPI determines the apoptosis response of non-small-cell lung cancer

et al. 2007

View full text Add to dashboard Cite

During malignant transformation, cancer cells have to evade cell-intrinsic tumor suppressor mechanisms including apoptosis, thus acquiring a phenotype that is relatively resistant to clinically applied anticancer therapies. Molecular characterization of apoptotic signal transduction defects may help to identify prognostic markers and to develop novel therapeutic strategies. To this end we have undertaken functional analyses of drug-induced apoptosis in human non-small cell-lung cancer (NSCLC) cells. We found that primary drug resistance correlated with defects in apoptosome-dependent caspase activation in vitro. While cytochrome c-induced apoptosome formation was maintained, the subsequent activation of caspase-9 and -3 was abolished in resistant NSCLC. The addition of recombinant pp32/putative human HLA class II-associated protein (pp32/PHAPI), described as a putative tumor suppressor in prostate cancer, successfully restored defective cytochrome c-induced caspase activation in vitro. Conditional expression of pp32/PHAPI sensitized NSCLC cells to apoptosis in vitro and in a murine tumor model in vivo. Immunohistochemical analyses of tumor samples from NSCLC patients revealed that the expression of pp32/PHAPI correlated with an improved outcome following chemotherapy. These results identify pp32/PHAPI as regulator of the apoptosis response of cancer cells in vitro and in vivo, and as a predictor of survival following chemotherapy for advanced NSCLC.

show abstract

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

Cited by 66 publications

References 35 publications

Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

Targeting BCL‐2 family proteins to overcome drug resistance in non‐small cell lung cancer

pp32/PHAPI determines the apoptosis response of non-small-cell lung cancer

Contact Info

Product

Resources

About