Massive Cell Death of Immature Hematopoietic Cells and Neurons in Bcl-x-Deficient Mice

Motoyama, Noboru; Wang, Fanping; Roth, Kevin A.; Sawa, Hirofumi; Nakayama, Kei Ichi; Nakayama, Keiko; Negishi, Izumi; Senju, Satoru; Zhang, Qing; Fujii, Satoshi; Loh, Dennis Y.

doi:10.1126/science.7878471

Cited by 1,087 publications

(747 citation statements)

References 34 publications

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“…The patterns and levels of expression of Bcl-2, Bcl-x L and Bcl-w are not identical (Hockenberry et al, 1991;LeBrun et al, 1993;Gonzalez-Garcia et al, 1994;Gibson et al, 1996) and these di erences may re¯ect the need to ®ne-tune the control of apoptosis in a cell type-and di erentiation type-speci®c manner. Consistent with this hypothesis Bcl-2-de®cient and Bcl-x-de®cient mice exhibit distinct phenotypic abnormalities (Veis et al, 1993;Motoyama et al, 1995).…”

Section: Discussionmentioning

confidence: 53%

Bcl-2, Bcl-xL and adenovirus protein E1B19kD are functionally equivalent in their ability to inhibit cell death

1997

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Section: Discussionmentioning

confidence: 53%

Bcl-2, Bcl-xL and adenovirus protein E1B19kD are functionally equivalent in their ability to inhibit cell death

1997

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“…Indeed, recent antisense experiments on explanted mesoderm cultures, using the same oligonucleotides developed for our studies (Bernasconi et al, 1996), con®rm that downregulation of Pax-3 results in increased apoptosis in vivo (Borycki et al, 1999). Embryos which are defective for Bcl-xl show embryonic lethality around day 13 of development with characterized defects in neuronal cells and lymphocytes (Motoyama et al, 1995). However, due to the early lethality, speci®c defects in the myogenic lineage might not have been analysed.…”

Section: Discussionmentioning

confidence: 77%

Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR

et al. 2000

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The aberrant expression of the transcription factors PAX3 and PAX3/FKHR associated with rhabdomyosarcoma (RMS), solid tumors displaying muscle cell features, suggests that these proteins play an important role in the pathogenesis of RMS. We could previously demonstrate that one of the oncogenic functions of PAX3 and PAX3/FKHR in RMS is protection from apoptosis. BCL-XL is a prominent anti-apoptotic protein present in normal skeletal muscle and RMS cells. In the present study, we establish that BCL-XL is transcriptionally modulated by PAX3 and PAX3/FKHR, since enhanced expression of both PAX proteins stimulates transcription of endogenous BCL-XL mRNA in a cell type speci®c manner. Further, we present evidence that both PAX3 and PAX3/FKHR can transcriptionally activate the Bcl-x gene promoter in cotransfection assays. Using electrophoretic mobility shift assays, an ATTA binding site for PAX3 and PAX3/FKHR could be localized in the upstream promoter region (position 742 to 739). Finally, ectopic overexpression of either PAX3, PAX3/FKHR or BCL-XL can rescue tumor cells from apoptosis induced by antisense treatment. These results suggest that at least part of the anti-apoptotic e ect of PAX3 and PAX3/FKHR is mediated through direct transcriptional modulation of the prominent antiapoptotic protein BCL-XL.

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“…The knockout mouse model showed that, as with Bcl11b, deficiency of Bcl-xL led to massive apoptosis of hematopoietic cells, and impaired maturation and shortened lifespan of lymphocytes (Motoyama et al, 1995). In turn, overexpression of Bcl-xL within the Tcell lineage resulted in accumulation of thymocytes in lymphoid organs and increased resistance to apoptosis (Grillot et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of BCL11B expression leads to apoptosis of malignant but not normal mature T cells

et al. 2006

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The B-cell chronic lymphocytic leukemia (CLL)/lymphoma 11B gene (BCL11B) encodes a Kru¨ppel-like zincfinger protein, which plays a crucial role in thymopoiesis and has been associated with hematopoietic malignancies. It was hypothesized that BCL11B may act as a tumorsuppressor gene, but its precise function has not yet been elucidated. Here, we demonstrate that the survival of human T-cell leukemia and lymphoma cell lines is critically dependent on Bcl11b. Suppression of Bcl11b by RNA interference selectively induced apoptosis in transformed T cells whereas normal mature T cells remained unaffected. The apoptosis was effected by simultaneous activation of death receptor-mediated and intrinsic apoptotic pathways, most likely as a result of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) upregulation and suppression of the Bcl-xL antiapoptotic protein. Our data indicate an antiapoptotic function of Bcl11b. The resistance of normal mature T lymphocytes to Bcl11b suppression-induced apoptosis and restricted expression pattern make it an attractive therapeutic target in T-cell malignancies.

show abstract

Massive Cell Death of Immature Hematopoietic Cells and Neurons in Bcl-x-Deficient Mice

Cited by 1,087 publications

References 34 publications

Bcl-2, Bcl-xL and adenovirus protein E1B19kD are functionally equivalent in their ability to inhibit cell death

Bcl-2, Bcl-xL and adenovirus protein E1B19kD are functionally equivalent in their ability to inhibit cell death

Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR

Inhibition of BCL11B expression leads to apoptosis of malignant but not normal mature T cells

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