Ikaros and Aiolos inhibit pre-B-cell proliferation by directly suppressing c-Myc expression.
Pre-B-cell expansion is driven by signals from the interleukin-7 receptor and the pre-B-cell receptor and is dependent on cyclin D3 and c-Myc. We have shown previously that interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to suppress pre-B-cell proliferation. However, the molecular mechanisms through which Ikaros and Aiolos exert their growth inhibitory effect remain to be determined. Here, we provide evidence that Aiolos and Ikaros bind to the c-Myc promoter in vivo and directly suppress c-Myc expression in pre-B cells. We further show that downregulation of c-Myc is critical for the growth-inhibitory effect of Ikaros and Aiolos. Ikaros and Aiolos also induce expression of p27 and downregulate cyclin D3 in pre-B cells, and the growth-inhibitory effect of Ikaros and Aiolos is compromised in the absence of p27. A time course analysis further reveals that downregulation of c-Myc by Ikaros and Aiolos precedes p27 induction and cyclin D3 downregulation. Moreover, downregulation of c-Myc by Ikaros and Aiolos is necessary for the induction of p27 and downregulation of cyclin D3. Collectively, our studies identify a pre-B-cell receptor signaling induced inhibitory network, orchestrated by Ikaros and Aiolos, which functions to terminate pre-B-cell expansion.
Ma
Shibin
S
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198-5805, USA.
Pathak
Simanta
S
Mandal
Malay
M
Trinh
Long
L
Clark
Marcus R
MR
Lu
Runqing
R
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D056743:Cyclin D3 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D051740:Ikaros Transcription Factor / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology* / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
D056743:Cyclin D3; C491396:Ikzf3 protein, mouse; D018809:Proliferating Cell Nuclear Antigen; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; C413374:p27 antigen; D051740:Ikaros Transcription Factor