Dual regulation of SPI1/PU.1 transcription factor by heat shock factor 1 (HSF1) during macrophage differentiation of monocytes.

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: In addition to their cytoprotective role in stressful conditions, heat shock proteins (HSPs) are involved in specific differentiation pathways, e.g. we have identified a role for HSP90 in macrophage differentiation of human peripheral blood monocytes exposed to Macrophage Colony-Stimulating Factor (M-CSF). Here, we show that deletion of the main transcription factor involved in heat shock gene regulation, heat shock factor 1 (HSF1), affects M-CSF-driven differentiation of mouse bone marrow cells. HSF1 transiently accumulates in the nucleus of human monocytes undergoing macrophage differentiation, including M-CSF-treated peripheral blood monocytes and phorbol ester-treated THP1 cells. We demonstrate that HSF1 has a dual effect on SPI1/PU.1, a transcription factor essential for macrophages differentiation and whose deregulation can lead to the development of leukemias and lymphomas. First, HSF1 regulates SPI1/PU.1 gene expression through its binding to a Heat Shock Element (HSE) within the intron 2 of this gene. Furthermore, down-regulation or inhibition of HSF1 impaired both SPI1/PU.1 targeted gene transcription and macrophage differentiation. Secondly, HSF1 induces the expression of HSP70 that interacts with SPI1/PU.1 to protect the transcription factor from proteasomal degradation. Taken together, HSF1 appears as a fine-tuning regulator of SPI1/PU.1 expression at the transcriptional and post-translational levels during macrophage differentiation of monocytes.Leukemia accepted article preview online, 7 February 2014; doi:10.1038/leu.2014.63.

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