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Abstract
Bcl-xL, a member of the Bcl-2 family, inhibits apoptosis, and its expression is regulated at the transcriptional level, yet nothing is known about the transcription factors specifically activating this promoter. The bcl-xpromoter contains potential Ets binding sites, and we show that the transcription factor, Ets2, first identified by its sequence identity to v-ets of the E26 retrovirus, can transactivate the bcl-x promoter. Transient expression of Ets2 results in the upregulation of Bcl-xL but not of Bcl-xS, an alternatively spliced gene product which induces apoptosis. Ets2 is ubiquitously expressed at low levels in a variety of cell types and tissues but is specifically induced to abundant levels during macrophage differentiation. Since Bcl-xL is also upregulated during macrophage differentiation, we asked whether the bcl-x could be a direct downstream target gene of Ets2 in macrophages. BAC1.2F5 macrophages, which are dependent on macrophage colony-stimulating factor 1 (CSF-1) for their growth and survival, were used in these studies. We show that CSF-1 stimulation of BAC1.2F5 macrophages results in the upregulation of expression of ets2 and bcl-xL with similar kinetics of induction. In the absence of CSF-1, these macrophages undergo cell death by apoptosis, whereas constitutive expression of Ets2 rescues these cells from cell death, and bcl-xL is upregulated. These results strongly suggest a novel role of Ets2 in affecting apoptosis through its regulation of Bcl-xL transcription.
ACKNOWLEDGMENTS
We thank M. Baccarini, J. Gautier, U. Hibner, S. Korsmeyer, and S. Gisselbrecht for kindly providing us with JE, IL-1,bcl-2, bcl-xL , and CSF-1 plasmids.
L.S. and C.A. contributed equally to this work.
L.S. is supported by EC grant ERBFMBICT972684. C.A. was supported during her Ph.D. work by fellowships from La Ligue Contre le Cancer and the Association pour la Recherche contre le Cancer, and C.B. and O.P were supported during their Master’s thesis work by the French Ministry. Grant support was provided to K.E.B. by La Ligue contre le Cancer and the Association pour la Recherche contre le Cancer (no. 9691), to P.P. by the Association pour la Recherche contre le Cancer (no. 1600), and to V.D. by ATIPE.