The transcriptional coregulator NAB2 is a target gene for the Wilms' tumor gene 1 protein (WT1) in leukemic cells
نویسندگان
چکیده
The Wilms' tumor gene 1 (WT1) is recurrently mutated in acute myeloid leukemia. Mutations and high expression of WT1 associate with a poor prognosis. In mice, WT1 cooperates with the RUNX1/RUNX1T1 (AML1/ETO) fusion gene in the induction of acute leukemia, further emphasizing a role for WT1 in leukemia development. Molecular mechanisms for WT1 are, however, incompletely understood. Here, we identify the transcriptional coregulator NAB2 as a target gene of WT1. Analysis of gene expression profiles of leukemic samples revealed a positive correlation between the expression of WT1 and NAB2, as well as a non-zero partial correlation. Overexpression of WT1 in hematopoietic cells resulted in increased NAB2 levels, while suppression of WT1 decreased NAB2 expression. WT1 bound and transactivated the proximal NAB2 promoter, as shown by ChIP and reporter experiments, respectively. ChIP experiments also revealed that WT1 can recruit NAB2 to the IRF8 promoter, thus modulating the transcriptional activity of WT1, as shown by reporter experiments. Our results implicate NAB2 as a previously unreported target gene of WT1 and that NAB2 acts as a transcriptional cofactor of WT1.
منابع مشابه
Over-expression of Wilm’s Tumor Gene 1 (WT1) in Iranian Patients with Acute Myeloblastic Leukemia
Background: The Wilm’s tumor gene 1 (WT1) encodes a zinc finger transcription factor that is inactivated in a subset of Wilm’s tumors. It plays a crucial role in growth, proliferation and development of some embryonic and adult organs. WT1 is expressed as a tumor associated antigen (TAA) in various types of solid and hematopoietic malignancies and can be employed as a useful marker for targeted...
متن کاملThe hematopoietic tumor suppressor interferon regulatory factor 8 (IRF8) is upregulated by the antimetabolite cytarabine in leukemic cells involving the zinc finger protein ZNF224, acting as a cofactor of the Wilms' tumor gene 1 (WT1) protein.
The transcription factor interferon regulatory factor-8 (IRF8) is highly expressed in myeloid progenitors, while most myeloid leukemias show low or absent expression. Loss of IRF8 in mice leads to a myeloproliferative disorder, indicating a tumor-suppressive role of IRF8. The Wilms tumor gene 1 (WT1) protein represses the IRF8-promoter. The zinc finger protein ZNF224 can act as a transcriptiona...
متن کاملIn silico screening of G-Quadruplex Structures in Wilms tumor 1 Gene Promoter
Introduction: X-ray diffraction studies have revealed that guanines in a DNA stands may be arranged in quartet and form a structure called G-quadruplexs. Bioinformatics studies suggested the formation of G-quadruplex structure in human crucial genes, including Wilms tumor 1 (WT1). The aim of this study was to in silico analysis of the guanine-rich sequence in the promoter region of the WT1 gene...
متن کاملWT1 induces expression of insulin-like growth factor 2 in Wilms' tumor cells.
The Wilms' tumor suppressor gene WT1 encodes a zinc finger transcription factor, whose expression inhibits the growth of the RM1 Wilms' tumor cell line. Transient transfection of WT1 constructs into 3T3 or 293 cells results in transcriptional repression of a number of cotransfected promoters containing the early growth response gene 1 consensus sequence. We now show that WT1 has properties of a...
متن کاملRole of the Wilms' tumor 1 gene in the aberrant biological behavior of leukemic cells and the related mechanisms.
The Wilms' tumor 1 (WT1) gene is one of the regulating factors in cell proliferation and development. It is a double-functional gene: an oncogene and a tumor suppressor. This gene was found to be highly expressed in many leukemic cell lines and in patients with acute myeloid leukemia. In the present study, we demonstrated that the WT1 gene was commonly expressed in leukemic cell lines apart fro...
متن کامل