Bcl-x(L) expression correlates with primary macrophage differentiation, activation of functional competence, and survival and results from synergistic transcriptional activation by Ets2 and PU.1
L. Sevilla et al., Bcl-x(L) expression correlates with primary macrophage differentiation, activation of functional competence, and survival and results from synergistic transcriptional activation by Ets2 and PU.1, J BIOL CHEM, 276(21), 2001, pp. 17800-17807
Depriving primary bone marrow-derived macrophages of colony-stimulating fac
tor-1 (CSF-1) induces programmed cell death by apoptosis, We show that cell
death is accompanied by decreases in the expression of anti-apoptotic Bcl-
x(L) protein and the Ets2 and PU.1 proteins of the Ets transcription factor
family. Macrophages require both priming and triggering signals independen
t of CSF-1 to kill neoplastic cells or microorganisms, and this activation
of macrophage competence is accompanied by increased expression of bcl-x(L)
, ets2, and PU.1. Furthermore, we show that only Ets2 and PU.1, but not Ets
1, function in a synergistic manner to transactivate the bcl-x promoter. Th
e synergy observed between PU.1 and Ets2 is dependent on the transactivatio
n domains of both proteins. Although other transcription factors like Foe,
c-Jun, Myc, STAT3, and STAT5a are implicated in the activation of macrophag
e competence or in CSF-1 signaling, no synergy was observed between Ets2 an
d these transcription factors on the bcl-x promoter. We demonstrate that th
e exogenous expression of both Ets2 and PU.1 in macrophages increases the n
umber of viable cells upon CSF-1 depletion and that Ets2 and PU.1 can funct
ionally replace Bcl-x(L) in inhibiting Bar-induced apoptosis, Together, the
se results demonstrate that PU.1 and Ets2 dramatically increase bcl-x activ
ation, which is necessary for the cytocidal function and survival of macrop
hages.