title: The role of the transcription factor Miz-1 in lymphocyte development and lymphomagenesis-Binding Myc makes the difference.
abstract: The Myc interacting zinc finger protein 1 (Miz-1) is a BTB/POZ domain containing transcription factor that can function as an activator or repressor depending on its binding partners. In a complex with co-factors such as nuclophosmin or p300, Miz-1 stimulates transcription of genes that encode regulators of cell cycle progression such as p21(Cip1) or p15(Ink4b) or inhibitors of apoptosis such as Bcl-2. In contrast, Miz-1 becomes a transcriptional repressor when it binds to c-Myc or Bcl-6, which replace nucleophosmin or p300. During lymphocyte development, Miz-1 functions as a regulator of the IL-7 signaling pathway at very early steps in the bone marrow and thymus. When the IL-7 receptor (IL-7R) recognizes its cognate cytokine, a cascade of events is initiated that involves the recruitment of janus kinases (JAK) to the cytoplasmic part of the IL-7R, the phosphorylation of Stat5, its dimerization and relocation to the nucleus, enabling a transcriptional programming that governs commitment, survival and proliferation of lymphoid lineage cells. Miz-1 is critical in this signal transduction pathway, since it controls the expression of Socs1, an inhibitor of JAKs and thus of Stat5 activation and Bcl-2 expression. A lack of Miz-1 blocks IL-7 mediated signaling, which is detrimental for early B- and T-lymphoid development. These functions of Miz-1 during early lymphocyte development are c-Myc-independent. In contrast, when c-Myc is constitutively over-expressed, for instance during c-Myc induced lymphomagenesis, the interaction between Miz-1 and c-Myc becomes important and critical for the initiation and maintenance of c-Myc-dependent lymphoid malignancies.
authors: Institut de recherches cliniques de Montréal - IRCM, 110 Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada. Tarik.Moroy@ircm.qc.ca
authors: Tarik
authors: T
authors: Möröy
authors: Ingrid
authors: I
authors: Saba
authors: Christian
authors: C
authors: Kosan
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008223:Lymphoma / Q000473:pathology*; D008954:Models, Biological; D051560:Proto-Oncogene Proteins c-bcl-6; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; C116115:MYCBP protein, human; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; C107961:ZBTB17 protein, human