DLEU2, frequently deleted in malignancy, functions as a critical host gene of the cell cycle inhibitory microRNAs miR-15a and miR-16-1
Abstract
The microRNAs miR-15a and miR-16-1 are downregulated in multiple tumor types and are frequently deleted in chronic lymphocytic leukemia (CLL), myeloma and mantle cell lymphoma. Despite their abundance in most cells the transcriptional regulation of miR-15a/16-1 remains unclear. Here we demonstrate that the putative tumor suppressor DLEU2 acts as a host gene of these microRNAs. Mature miR-15a/miR-16-1 are produced in a Drosha-dependent process from DLEU2 and binding of the Myc oncoprotein to two alterative DLEU2 promoters represses both the host gene transcript and levels of mature miR-15a/miR-16-1. In line with a functional role for DLEU2 in the expression of the microRNAs, the miR-15a/miR-16-1 locus is retained in four CLL cases that delete both promoters of this gene and expression analysis indicates that this leads to functional loss of mature miR-15a/16-1. We additionally show that DLEU2 negatively regulates the G1 Cyclins E1 and D1 through miR-15a/miR-16-1 and provide evidence that these oncoproteins are subject to miR-15a/miR-16-1-mediated repression under normal conditions. We also demonstrate that DLEU2 overexpression blocks cellular proliferation and inhibits the colony-forming ability of tumor cell lines in a miR-15a/miR-16-1-dependent way. Together the data illuminate how inactivation of DLEU2 promotes cell proliferation and tumor progression through functional loss of miR-15a/miR-16-1.
- Authors:
-
- Department of Oncology-Pathology, Cancercentrum Karolinska (CCK), Karolinska Institutet R8:03, 171 76 Stockholm (Sweden)
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm (Sweden)
- Department of Pathology, Royal Bournemouth Hospital, Bournemouth (United Kingdom)
- Publication Date:
- OSTI Identifier:
- 22209828
- Resource Type:
- Journal Article
- Journal Name:
- Experimental Cell Research
- Additional Journal Information:
- Journal Volume: 315; Journal Issue: 17; Other Information: Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; CELL CYCLE; CELL PROLIFERATION; GENES; INACTIVATION; LEUKEMIA; LYMPHOMAS; PROMOTERS; TUMOR CELLS
Citation Formats
Lerner, Mikael, Harada, Masako, Loven, Jakob, Castro, Juan, Davis, Zadie, Oscier, David, Henriksson, Marie, Sangfelt, Olle, Grander, Dan, and Corcoran, Martin M. DLEU2, frequently deleted in malignancy, functions as a critical host gene of the cell cycle inhibitory microRNAs miR-15a and miR-16-1. United States: N. p., 2009.
Web. doi:10.1016/J.YEXCR.2009.07.001.
Lerner, Mikael, Harada, Masako, Loven, Jakob, Castro, Juan, Davis, Zadie, Oscier, David, Henriksson, Marie, Sangfelt, Olle, Grander, Dan, & Corcoran, Martin M. DLEU2, frequently deleted in malignancy, functions as a critical host gene of the cell cycle inhibitory microRNAs miR-15a and miR-16-1. United States. https://doi.org/10.1016/J.YEXCR.2009.07.001
Lerner, Mikael, Harada, Masako, Loven, Jakob, Castro, Juan, Davis, Zadie, Oscier, David, Henriksson, Marie, Sangfelt, Olle, Grander, Dan, and Corcoran, Martin M. 2009.
"DLEU2, frequently deleted in malignancy, functions as a critical host gene of the cell cycle inhibitory microRNAs miR-15a and miR-16-1". United States. https://doi.org/10.1016/J.YEXCR.2009.07.001.
@article{osti_22209828,
title = {DLEU2, frequently deleted in malignancy, functions as a critical host gene of the cell cycle inhibitory microRNAs miR-15a and miR-16-1},
author = {Lerner, Mikael and Harada, Masako and Loven, Jakob and Castro, Juan and Davis, Zadie and Oscier, David and Henriksson, Marie and Sangfelt, Olle and Grander, Dan and Corcoran, Martin M.},
abstractNote = {The microRNAs miR-15a and miR-16-1 are downregulated in multiple tumor types and are frequently deleted in chronic lymphocytic leukemia (CLL), myeloma and mantle cell lymphoma. Despite their abundance in most cells the transcriptional regulation of miR-15a/16-1 remains unclear. Here we demonstrate that the putative tumor suppressor DLEU2 acts as a host gene of these microRNAs. Mature miR-15a/miR-16-1 are produced in a Drosha-dependent process from DLEU2 and binding of the Myc oncoprotein to two alterative DLEU2 promoters represses both the host gene transcript and levels of mature miR-15a/miR-16-1. In line with a functional role for DLEU2 in the expression of the microRNAs, the miR-15a/miR-16-1 locus is retained in four CLL cases that delete both promoters of this gene and expression analysis indicates that this leads to functional loss of mature miR-15a/16-1. We additionally show that DLEU2 negatively regulates the G1 Cyclins E1 and D1 through miR-15a/miR-16-1 and provide evidence that these oncoproteins are subject to miR-15a/miR-16-1-mediated repression under normal conditions. We also demonstrate that DLEU2 overexpression blocks cellular proliferation and inhibits the colony-forming ability of tumor cell lines in a miR-15a/miR-16-1-dependent way. Together the data illuminate how inactivation of DLEU2 promotes cell proliferation and tumor progression through functional loss of miR-15a/miR-16-1.},
doi = {10.1016/J.YEXCR.2009.07.001},
url = {https://www.osti.gov/biblio/22209828},
journal = {Experimental Cell Research},
issn = {0014-4827},
number = 17,
volume = 315,
place = {United States},
year = {Thu Oct 15 00:00:00 EDT 2009},
month = {Thu Oct 15 00:00:00 EDT 2009}
}