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

Tschan, Mario P.; Federzoni, Elena A.; Haimovici, Aladin; Britschgi, Christian; Moser, Bettina A.; Jin, Jing; Reddy, Venkateshwar A.; Sheeter, Dennis A.; Fischer, Kimberlee M.; Sun, Peiqing; Torbett, Bruce E. (2015). Human DMTF1β antagonizes DMTF1α regulation of the p14(ARF) tumor suppressor and promotes cellular proliferation. Biochimica et biophysica acta - gene regulatory mechanisms, 1849(9), pp. 1198-1208. Elsevier 10.1016/j.bbagrm.2015.07.009

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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 dose-dependent inhibition of DMP1α-induced transactivation of the ARF promoter. Ectopic expression of DMP1β reduced endogenous ARF mRNA levels in human fibroblasts. The DMP1β- and γ-isoforms share domains necessary for the inhibitory function of the β-isoform. That DMP1β may interact with DMP1α to antagonize its function was shown in DNA binding assays and in cells by the close proximity of DMP1α/β in the nucleus. Cells stably expressing DMP1β, 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 DMP1α- and β-ratios are tightly regulated in hematopoietic cells and DMP1β antagonizes DMP1α transcriptional regulation of ARF resulting in the alteration of cellular control with a gain in proliferation.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Tschan, Mario; Haimovici, Aladin and Jin, Jing

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1874-9399

Publisher:

Elsevier

Language:

English

Submitter:

Doris Haefelin

Date Deposited:

07 Dec 2015 12:02

Last Modified:

29 May 2017 17:44

Publisher DOI:

10.1016/j.bbagrm.2015.07.009

PubMed ID:

26187004

Uncontrolled Keywords:

ARF Human DMP1 Human DMTF1 Leukemia p14(ARF) p53

BORIS DOI:

10.7892/boris.73733

URI:

https://boris.unibe.ch/id/eprint/73733

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