Abstract
The ETS domain transcription factor PU.1 is necessary for the development of monocytes and regulates, in particular, the expression of the monocyte-specific macrophage colony-stimulating factor (M-CSF) receptor, which is critical for monocytic cell survival, proliferation, and differentiation. The bZIP transcription factor c-Jun, which is part of the AP-1 transcription factor complex, is also important for monocytic differentiation, but the monocyte-specific M-CSF receptor promoter has no AP-1 consensus binding sites. We asked the question of whether c-Jun could promote the induction of the M-CSF receptor by collaborating with PU.1. We demonstrate that c-Jun enhances the ability of PU.1 to transactivate the M-CSF receptor promoter as well as a minimal thymidine kinase promoter containing only PU.1 DNA binding sites. c-Jun does not directly bind to the M-CSF receptor promoter but associates via its basic domain with the ETS domain of PU.1. Consistent with our observation that AP-1 binding does not contribute to c-Jun coactivation is the observation that the activation of PU.1 by c-Jun is blocked by overexpression of c-Fos. Phosphorylation of c-Jun by c-Jun NH2-terminal kinase on Ser-63 and -73 does not alter the ability of c-Jun to enhance PU.1 transactivation. Activated Ras enhances the transcriptional activity of PU.1 by up-regulating c-Jun expression without changing the phosphorylation pattern of PU.1. The activation of PU.1 by Ras is blocked by a mutant c-Jun protein lacking the basic domain. The expression of this mutant form of c-Jun also completely blocks 12-O-tetradecanoylphorbol-13-acetate-induced M-CSF receptor promoter activity during monocytic differentiation. We propose therefore that c-Jun acts as a c-Jun NH2-terminal kinase-independent coactivator of PU.1, resulting in M-CSF receptor expression and development of the monocytic lineage.
Highlights
The ETS domain transcription factor PU.1 is preferentially expressed in myeloid and B cells [1, 2] and plays a pivotal role in their development [3, 4]
There is evidence that c-Jun plays a role in monocytic differentiation. c-Jun mRNA is up-regulated upon monocyte differentiation of bipotential myeloid cell lines (20 –22), while stable transfection of c-Jun into myeloid cell lines results in partial differentiation [23, 24]
We demonstrate that c-Jun enhances the ability of PU.1 to transactivate the human monocyte-specific macrophage colony-stimulating factor (M-CSF) receptor promoter (Fig. 1, A and B)
Summary
M-CSF, macrophage colony-stimulating factor; TPA, 12-O-tetradecanoylphorbol-13-acetate; bp, base pair(s); GST, glutathione S-transferase; TK, thymidine kinase. C-Jun Is a Coactivator of PU. no AP-1 consensus binding sites. As c-Jun and the regulation of the M-CSF receptor by PU. play important roles in monocytic differentiation, we hypothesized that c-Jun might be involved in the regulation of the M-CSF receptor, not by binding to AP-1 sites, but possibly via a novel mechanism. We asked the question of whether c-Jun modulates the ability of PU. to transactivate the human monocyte specific M-CSF receptor promoter
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
