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Human DMTF1? antagonizes DMTF1? regulation of the p14(ARF) tumor suppressor and promotes cellular proliferation.

ABSTRACT: 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, ?, ? and ?, arise from the human gene. We now show that DMP1?, ? and ? isoforms differentially regulate ARF expression and promote distinct cellular functions. In contrast to DMP1?, DMP1? and ? did not activate the ARF promoter, whereas only ? resulted in a dose-dependent inhibition of DMP1?-induced transactivation of the ARF promoter. Ectopic expression of DMP1? reduced endogenous ARF mRNA levels in human fibroblasts. The DMP1?- and ?-isoforms share domains necessary for the inhibitory function of the ?-isoform. That DMP1? may interact with DMP1? to antagonize its function was shown in DNA binding assays and in cells by the close proximity of DMP1?/? in the nucleus. Cells stably expressing DMP1?, as well as shRNA targeting all DMP1 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 acid promoted differentiation to granulocytes and restored DMP1 transcripts to normal granulocyte levels. Our findings imply that DMP1?- and ?-ratios are tightly regulated in hematopoietic cells and DMP1? antagonizes DMP1? transcriptional regulation of ARF resulting in the alteration of cellular control with a gain in proliferation.

SUBMITTER: Tschan MP

PROVIDER: S-EPMC4687731 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Human DMTF1β antagonizes DMTF1α regulation of the p14(ARF) tumor suppressor and promotes cellular proliferation.

Tschan Mario P MP Federzoni Elena A EA Haimovici Aladin A Britschgi Christian C Moser Bettina A BA Jin Jing J Reddy Venkateshwar A VA Sheeter Dennis A DA Fischer Kimberlee M KM Sun Peiqing P Torbett Bruce E BE

Biochimica et biophysica acta 20150715 9

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, α, β and γ, arise from the human gene. We now show that DMP1α, β and γ isoforms differentially regulate ARF expression and promote distinct cellular functions. In contrast to DMP1α, DMP1β and γ did not activate the ARF promoter, whereas only β resulted in a ...[more]

PMID: 26187004

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Project description:Background & Aims:Uncontrolled liver proliferation is a key characteristic of liver cancer; however, the mechanisms by which this occurs are not well understood. Elucidation of these mechanisms is necessary for the development of better therapy. The oncogene Gankyrin (Gank) is overexpressed in both hepatocellular carcinoma and hepatoblastoma. The aim of this work was to determine the role of Gank in liver proliferation and elucidate the mechanism by which Gank promotes liver proliferation. Methods:We generated Gank liver-specific knock-out (GLKO) mice and examined liver biology and proliferation after surgical resection and liver injury. Results:Global profiling of gene expression in GLKO mice showed significant changes in pathways involved in liver cancer and proliferation. Investigations of liver proliferation after partial hepatectomy and CCl4 treatment showed that GLKO mice have dramatically inhibited proliferation of hepatocytes at early stages after surgery and injury. In control LoxP mice, liver proliferation was characterized by Gank-mediated reduction of tumor-suppressor proteins (TSPs). The failure of GLKO hepatocytes to proliferate is associated with a lack of down-regulation of these proteins. Surprisingly, we found that hepatic progenitor cells of GLKO mice start proliferation at later stages and restore the original size of the liver at 14 days after partial hepatectomy. To examine the proliferative activities of Gank in cancer cells, we used a small molecule, cjoc42, to inhibit interactions of Gank with the 26S proteasome. These studies showed that Gank triggers degradation of TSPs and that cjoc42-mediated inhibition of Gank increases levels of TSPs and inhibits proliferation of cancer cells. Conclusions:These studies show that Gank promotes hepatocyte proliferation by elimination of TSPs. This work provides background for the development of Gank-mediated therapy for the treatment of liver cancer. RNA sequencing data can be accessed in the NCBI Gene Expression Omnibus: GSE104395.

Dataset Information

Human DMTF1? antagonizes DMTF1? regulation of the p14(ARF) tumor suppressor and promotes cellular proliferation.

Publications

Human DMTF1β antagonizes DMTF1α regulation of the p14(ARF) tumor suppressor and promotes cellular proliferation.

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