The MN1 oncoprotein activates transcription of the IGFBP5 promoter through a CACCC-rich consensus sequence.
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.
Meester-Smoor
Magda A
MA
Department of Pathology, Erasmus MC-Josephine Nefkens Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
Molijn
Anco C
AC
Zhao
Yixian
Y
Groen
Nicole A
NA
Groffen
Cora A H
CA
Boogaard
Merel
M
van Dalsum-Verbiest
Diny
D
Grosveld
Gerard C
GC
Zwarthoff
Ellen C
EC
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D016384:Consensus Sequence / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000096:biosynthesis / Q000235:genetics*; D008579:Meningioma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000502:physiology*; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
D018975:Insulin-Like Growth Factor Binding Protein 5; C506524:MN1 protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins