The MN1 oncoprotein activates transcription of the IGFBP5 promoter through a CACCC-rich consensus sequence

Abstract

The IGF-binding protein (IGFBP) family consists of six proteins that are expressed and secreted in different tissues. The proteins are regulators of physiological processes throughout the body by modulating the activity of IGF-I and IGF-II. In this article, we describe the coordinated expression of IGFBP5 and MN1 in meningiomas. MN1 is a transcriptional co-activator and we show that MN1 stimulates the IGFBP5 promoter in Hep3B cells. A CACCC-containing sequence, located 140 bp upstream of the transcription start site of the promoter, is required for MN1 action. This sequence matches with the CACCCAC consensus sequence that was selected in an oligonucleotide selection assay performed for MN1. The CACCC element has also been shown to be important for induction of the IGFBP5 promoter by retinoic acid (RA) and progesterone (Pg). We were unable to confirm the effect of Pg on the promoter in Hep3B and U2-osteosarcoma cells regardless of the presence of MN1. On the other hand, we show that induction of the promoter by RA depends on co-expressed MN1 in Hep3B cells. MN1TEL, a leukemia-related fusion protein containing parts of the MN1 and TEL (ETV6) genes, is capable of stimulating the IGFBP5 promoter but is unable to cooperate with RA in Hep3B cells. This suggests that the effects of RA can be negatively affected in leukemias caused by MN1TEL.

Nuclear Receptor CAR Requires Early Growth Response 1 to Activate the Human Cytochrome P450 2B6 Gene

“…This protein binding to the Ϫ253/ Ϫ242 probe appeared only after OA treatment and remained after TCPOBOP and OA co-treatment. Based on the nucleotide sequence CACCCACACA, various transcription factors, such as SP1, AP1, Kruppel-like factors, and EGR1, were selected (16,17) and tested for their binding to the Ϫ253/Ϫ242 probe; only the EGR1 antibody supershifted the specific band (Fig. 4B).…”

Establishment of a novel human myeloid leukemia cell line, AMU‐AML1, carrying t(12;22)(p13;q11) without chimeric MN1‐TEL and with high expression of MN1

“…were correlated to a poor prognosis in patients with AML, and MN1 overexpression induced myeloid malignancy in mice (Heuser et al, 2007;Meester-Smoor et al, 2007). Therefore, MN1 expression in AMU-AML1 cells might play a role in the disease progression and possibly in leukemogenesis.…”

“…Many genes have been reported as fusion partners for TEL; these fusion partners include AML1, PDGFbR, MN1, ABL, MDS1/EVI1, JAK2, and others (Bohlander, 2005). The MN1 gene is located on chromosomal band 22p11, and the product of MN1 is associated with leukemogenesis as a coactivator of transcription (van Wely et al, 2003;Heuser et al, 2007;Meester-Smoor et al, 2007). A high level of MN1 mRNA expression is predictive of a poor outcome in patients with acute myeloid leukemia (AML) with normal karyotype (Heuser et al, 2006;Langer et al, 2009).…”

Genomic and transcriptome analysis revealing an oncogenic functional module in meningiomas

“…24 We also found that the IGFBP5 gene (whose promoter transcription can be activated by the MN1 gene product) was significantly suppressed (Table S1). 31 Interestingly, MN1 can both stimulate and inhibit transcription of this gene. Overexpression of MN1 was also reported in the development of acute myeloid leukemia.…”

“…IGFBP5 is also upregulated by MN1 and linked to other cancer types, including glioblastoma multiforme. 31,49 We further identified a core region within the oncogenic coexpression module, consisting of the hub genes GAB2 and KLF2. The additional hub genes ID1 and CTF1 were directly connected to these members of the core region.…”