The Ets2 transcription factor inhibits apoptosis induced by colony-stimulating factor 1 deprivation of macrophages through a Bcl-x(L)-dependent mechanism

Bcl-x(L), a member of the Bcl-2 family, inhibits apoptosis, and its express ion is regulated at the transcriptional level, yet nothing is known about t he transcription factors specifically activating this promoter, The bcl-x p ro meter contains potential Ets binding sites, and we show that the transcr iption factor, Ets2, first identified by its sequence identity to v-ets of the E26 retrovirus, can transactivate the bcl-x promoter, Transient express ion of Ets2 results in the upregulation of Bcl-x(L) bat not of Bcl-x(S), an alternatively spliced gene product which induces apoptosis, Ets2 is ubiqui tously expressed at low levels in a variety of cell types and tissues but i s specifically induced to abundant levels during macrophage differentiation . Since Bcl-x(L) 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 colon y-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 resul ts in the upregulation of expression of ets2 and bcl-x(L) with similar kine tics of induction. In the absence of CSF-1, these macrophages undergo cell death by apoptosis, whereas constitutive expression of Ets2 rescues these c ells from cell death, and bcl-x(L) is upregulated. These results strongly s uggest a novel role of Ets2 in affecting apoptosis through its regulation o f Bcl-x(L) transcription.