Medizinische Universität Graz - Research portal

• Go directly to the nagivation.
• Go directly to the content.

• Print view.
• German.
• Contact.
• Data entry.
• Start.
• Open Access.

Identification and functional characterisation of Nuclear Orphan Receptors as Tumor Suppressor Genes in aggressive non-Hodgkin`s Lymphomas and acute lymphoblastic leukemia

Abstract

NR4A1 (also called Nur77, TR3, or NGFI-B), NR4A2 (Nurr1 or RNR-1) and NR4A3 (Nor-1 or Minor) are three members of an orphan nuclear hormone receptor family referred to as Nur77 family. They are all transcription factors belonging to the superfamily of steroid nuclear hormone receptors. These nuclear hormone receptors (NR) are classified as early response genes, are induced by a diverse range of signals, including fatty acids, stress, growth factors, cytokines, peptide hormones, neurotransmitters, and physical stimuli for example magnetic fields or shear stress. In line with the pleiotropic physiological stimuli that induce the NR4A subgroup, these orphan NRs have been implicated in cell cycle regulation, apoptosis, inflammation, atherogenesis and more recently in carcinogenesis.
The ultimate growth of a tumour depends on not only the rate of tumour cell proliferation, but also the rate of tumour cell death (=apoptosis). NR4A1 controls both survival and death of cancer cells.
In contrast to NR4A1, only pro-survival effects, but not pro-apoptotic effects, have been reported for NR4A2.
NR4A3 has been shown to be functionally redundant with NR4A1 in T-cell apoptosis. Results also suggest that NR4A1 and NR4A3 have non-redundant functions as well.
The most convincing evidence that nuclear orphan receptors function as critical tumor suppressors is the observation that the abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to rapid development of acute myeloid leukemia. Evidence of nuclear orphan receptors acting as tumor suppressor genes in B-cell malignancies comes from the observation that Epstein-Barr virus EBNA 2 blocks NR4A1 mediated apoptosis in B-cells and from gene expression profiling in diffuse large B-cell lymphoma (DLBCL) in which over expression of NR4A3 is found in cured or refractory DLBCL, as opposed to a fatal course of disease. Hence, it is speculated that NR4A3 increases the apoptotic response to chemotherapy in curable DLBCL.

The aim of our study was to comprehensively study NR expression and function in B-cell malignancies and to define the nuclear orphan receptors NR4A1 and NR4A1 as cooperative putative tumor suppressor genes (TSG) in B-cell malignancies.

Project Leader:

Neumeister Peter

Duration:

01.10.2008-30.09.2010

Type of Research

basic research

Staff

Neumeister, Peter, Project Leader

MUG Research Units

Division of Haematology

Funded by

Fellinger Krebsforschung (gemeinnütziger Verein), Wien, Austria