Bcl-XL expression correlates with primary macrophage differentiation, activation of functional competence, and survival and results from synergistic transcriptional activation by Ets2 and PU.1.
Depriving primary bone marrow-derived macrophages of colony-stimulating factor-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 independent 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 Ets1, function in a synergistic manner to transactivate the bcl-x promoter. The synergy observed between PU.1 and Ets2 is dependent on the transactivation domains of both proteins. Although other transcription factors like Fos, c-Jun, Myc, STAT3, and STAT5a are implicated in the activation of macrophage competence or in CSF-1 signaling, no synergy was observed between Ets2 and these transcription factors on the bcl-x promoter. We demonstrate that the exogenous expression of both Ets2 and PU.1 in macrophages increases the number of viable cells upon CSF-1 depletion and that Ets2 and PU.1 can functionally replace Bcl-x(L) in inhibiting Bax-induced apoptosis. Together, these results demonstrate that PU.1 and Ets2 dramatically increase bcl-x activation, which is necessary for the cytocidal function and survival of macrophages.
Sevilla
L
L
Institute of Signalisation, Developmental Biology and Cancer, INSERM 470, Centre de Biochimie, Université de Nice, Faculté des Sciences, 06108 Nice, France.
Zaldumbide
A
A
Carlotti
F
F
Dayem
M A
MA
Pognonec
P
P
Boulukos
K E
KE
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D004268:DNA-Binding Proteins; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D051379:Mice; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D012097:Repressor Proteins; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors; D015533:Transcriptional Activation; D014162:Transfection; D051020:bcl-X Protein; D000099232:Proto-Oncogene Protein Spi-1
D004268:DNA-Binding Proteins; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051020:bcl-X Protein; D000099232:Proto-Oncogene Protein Spi-1; C494812:Bcl2l1 protein, mouse; C107465:ERF protein, human; C494070:Ets2 protein, mouse