TY - JOUR
T1 - CD74 as a regulator of transcription in normal B cells
AU - David, Keren
AU - Friedlander, Gilgi
AU - Pellegrino, Bianca
AU - Radomir, Lihi
AU - Lewinsky, Hadas
AU - Leng, Lin
AU - Bucala, Richard
AU - Becker-Herman, Shirly
AU - Shachar, Idit
PY - 2022/11/1
Y1 - 2022/11/1
N2 - CD74 is receptor for the cytokine macrophage migration inhibitory factor (MIF). MIF binding to CD74 induces a signaling cascade resulting in the release of its cytosolic intracellular domain (CD74-ICD) that serves as a transcriptional regulator in chronic lymphocytic leukemia (CLL) cells. In the current study, we investigated the transcriptional and regulatory function of CD74-ICD in normal B cells. We show that following activation, CD74-ICD forms a complex in the cytosol with transcription factors, like PAX5, and binds the chromatin at a significantly higher number of sites compared with its binding in CLL cells. The expression of a major portion of these bound genes is shut down in the malignant cells. The CD74-ICD:PAX5 complex binds the promoter areas of a tumor-suppressor gene, DMTF1, and downregulates its expression through inhibition of transcription. These findings can help identify novel therapeutic pathways that are regulated during oncogenic transformation and are targets for future treatments.
AB - CD74 is receptor for the cytokine macrophage migration inhibitory factor (MIF). MIF binding to CD74 induces a signaling cascade resulting in the release of its cytosolic intracellular domain (CD74-ICD) that serves as a transcriptional regulator in chronic lymphocytic leukemia (CLL) cells. In the current study, we investigated the transcriptional and regulatory function of CD74-ICD in normal B cells. We show that following activation, CD74-ICD forms a complex in the cytosol with transcription factors, like PAX5, and binds the chromatin at a significantly higher number of sites compared with its binding in CLL cells. The expression of a major portion of these bound genes is shut down in the malignant cells. The CD74-ICD:PAX5 complex binds the promoter areas of a tumor-suppressor gene, DMTF1, and downregulates its expression through inhibition of transcription. These findings can help identify novel therapeutic pathways that are regulated during oncogenic transformation and are targets for future treatments.
UR - http://www.scopus.com/inward/record.url?scp=85140996422&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2022.111572
DO - 10.1016/j.celrep.2022.111572
M3 - Article
SN - 2211-1247
VL - 41
JO - Cell reports (Cambridge)
JF - Cell reports (Cambridge)
IS - 5
M1 - 111572
ER -