Human Dmtf1 Beta Antagonizes Dmtf1 Alpha Regulation Of The P14(Arf) Tumor Suppressor And Promotes Cellular Proliferation

The human DMTF1 (DMP1) transcription factor, a DNA binding protein that interacts with cyclin D, is a positive regulator of the p14ARF (ARF) tumor suppressor. Our earlier studies have shown that three differentially spliced human DMP1 mRNAs, alpha,beta,and gamma, arise from the human gene. We now show that DMP1 alpha, beta and gamma isoforms differentially regulate ARE expression and promote distinct cellular functions. In contrast to DMP1 alpha, DMP1 beta and gamma did not activate the ARF promoter, whereas only beta resulted in a dose-dependent inhibition of DMP1 alpha-induced transactivation of the ARF promoter. Ectopic expression of DMP1 beta reduced endogenous ARF mRNA levels in human fibroblasts. The DMP1 beta- and gamma-isoforms share domains necessary for the inhibitory function of the beta-isoform. That DMP1 beta may interact with DMP1 alpha to antagonize its function was shown in DNA binding assays and in cells by the close proximity of DMP1 alpha/beta in the nucleus. Cells stably expressing DMP1 beta, as well as shRNA targeting all DMPI isoforms, disrupted cellular growth arrest induced by serum deprivation or in PMA-derived macrophages in the presence or absence of cellular p53. DMP1 mRNA levels in acute myeloid leukemia samples, as compared to granulocytes, were reduced. Treatment of acute promyelocytic leukemia patient samples with all-trans retinoic add promoted differentiation to granulocytes and restored DMPI transcripts to normal granulocyte levels. Our findings imply that DMP1 alpha- and beta-ratios are tightly regulated in hematopoietic cells and DMP1 beta antagonizes DMP1 alpha transcriptional regulation of ARF resulting in the alteration of cellular control with a gain in proliferation. (C) 2015 Elsevier B.V. All rights reserved.