Ski can negatively regulates macrophage differentiation through its interaction with PU.1

• Published in: Oncogene Vol. 27; no. 3; pp. 300 - 307
• Main Authors: Ueki, N, Zhang, L, Haymann, M J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.01.2008; Nature Publishing; Nature Publishing Group
• Subjects: Animals; Apoptosis; Biological and medical sciences; Care and treatment; Cell Biology; Cell differentiation; Cell Differentiation - genetics; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cells; Cells, Cultured; Cellular signal transduction; Colony-stimulating factor; Development and progression; DNA binding proteins; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Leukemic; Genetic aspects; Health aspects; Hematology; Histone deacetylase; Histone Deacetylases - metabolism; Human Genetics; Humans; Internal Medicine; Leukemia; Leukemogenesis; Macrophage colony-stimulating factor; Macrophages - cytology; Macrophages - immunology; Medicine; Medicine & Public Health; Molecular and cellular biology; Molecular genetics; Myelocytic leukemia; Myeloid cells; Myeloid leukemia; Nonlymphoid leukemia; Oncology; original-article; Physiological aspects; Promoter Regions, Genetic; Proteins; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; PU.1 protein; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - analysis; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Risk factors; Ski protein; Trans-Activators - antagonists & inhibitors; Trans-Activators - metabolism; Transcription activation; Transcription factors; Transcription. Transcription factor. Splicing. Rna processing; United States; hematopoiesis; leukemogenesis; HDAC3; transcriptional repression; ski oncoprotein; PU.1; Transcription; Repression; Carcinogenesis; Regulation(control); Hematopoiesis; C-Onc gene; Differentiation; Onc gene; Macrophage
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210654

In the hematopoietic cell system, the oncoprotein Ski dramatically affects growth and differentiation programs, in some cases leading to malignant leukemia. However, little is known about the interaction partners or signaling pathways involved in the Ski-mediated block of differentiation in hematopoietic cells. Here we show that Ski interacts with PU.1, a lineage-specific transcription factor essential for terminal myeloid differentiation, and thereby represses PU.1-dependent transcriptional activation. Consistent with this, Ski inhibits the biological function of PU.1 to promote myeloid cells to differentiate into macrophage colony-stimulating factor receptor (M-CSFR)-positive macrophages. Using a Ski mutant deficient in PU.1 binding, we demonstrate that Ski–PU.1 interaction is critical for Ski's ability to repress PU.1-dependent transcription and block macrophage differentiation. Furthermore, we provide evidence that Ski-mediated repression of PU.1 is due to Ski's ability to recruit histone deacetylase 3 to PU.1 bound to DNA. Since inactivation of PU.1 is closely related to the development of myeloid leukemia and Ski strongly inhibits PU.1 function, we propose that aberrant Ski expression in certain types of myeloid cell lineages might contribute to leukemogenesis.