Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
GoGreen Membership

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Logo for

Genes & Dev. 20 (16): 2202-2207

Copyright © 2006 by Cold Spring Harbor Laboratory Press.


RESEARCH COMMUNICATION

Extensive post-transcriptional regulation of microRNAs and its implications for cancer

J. Michael Thomson1, Martin Newman1, Joel S. Parker4, Elizabeth M. Morin-Kensicki1, Tricia Wright2, and Scott M. Hammond1,3,5

1 Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA;
2 Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA;
3 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA;
4 Constella Group, Durham, North Carolina 27713, USA

Abstract: MicroRNAs (miRNAs) are short, noncoding RNAs that post-transcriptionally regulate gene expression. While hundreds of mammalian miRNA genes have been identified, little is known about the pathways that regulate the production of active miRNA species. Here we show that a large fraction of miRNA genes are regulated post-transcriptionally. During early mouse development, many miRNA primary transcripts, including the Let-7 family, are present at high levels but are not processed by the enzyme Drosha. An analysis of gene expression in primary tumors indicates that the widespread down-regulation of miRNAs observed in cancer is due to a failure at the Drosha processing step. These data uncover a novel regulatory step in miRNA function and provide a mechanism for miRNA down-regulation in cancer.

Key Words: miRNA • microRNA • let-7 • RISC • Drosha • cancer

Received for publication April 27, 2006. Accepted for publication June 14, 2006.


5 Corresponding author.

E-MAIL hammond{at}med.unc.edu; FAX (919) 966-1856.

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1444406.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
An Insect Virus-Encoded MicroRNA Regulates Viral Replication.
M. Hussain, R. J. Taft, and S. Asgari (2008)
J. Virol. 82, 9164-9170
   Abstract »    Full Text »    PDF »
The FLYWCH transcription factors FLH-1, FLH-2, and FLH-3 repress embryonic expression of microRNA genes in C. elegans.
M. C. Ow, N. J. Martinez, P. H. Olsen, H. S. Silverman, M. I. Barrasa, B. Conradt, A. J.M. Walhout, and V. Ambros (2008)
Genes & Dev. 22, 2520-2534
   Abstract »    Full Text »    PDF »
Frequency and fate of microRNA editing in human brain.
Y. Kawahara, M. Megraw, E. Kreider, H. Iizasa, L. Valente, A. G. Hatzigeorgiou, and K. Nishikura (2008)
Nucleic Acids Res. 36, 5270-5280
   Abstract »    Full Text »    PDF »
Role of microRNAs in vascular diseases, inflammation, and angiogenesis.
C. Urbich, A. Kuehbacher, and S. Dimmeler (2008)
Cardiovasc Res 79, 581-588
   Abstract »    Full Text »    PDF »
Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing.
M. A. Newman, J. M. Thomson, and S. M. Hammond (2008)
RNA 14, 1539-1549
   Abstract »    Full Text »    PDF »
Genomic Profiling of MicroRNA and Messenger RNA Reveals Deregulated MicroRNA Expression in Prostate Cancer.
S. Ambs, R. L. Prueitt, M. Yi, R. S. Hudson, T. M. Howe, F. Petrocca, T. A. Wallace, C.-G. Liu, S. Volinia, G. A. Calin, et al. (2008)
Cancer Res. 68, 6162-6170
   Abstract »    Full Text »    PDF »
Diagnostic and Prognostic MicroRNAs in Stage II Colon Cancer.
T. Schepeler, J. T. Reinert, M. S. Ostenfeld, L. L. Christensen, A. N. Silahtaroglu, L. Dyrskjot, C. Wiuf, F. J. Sorensen, M. Kruhoffer, S. Laurberg, et al. (2008)
Cancer Res. 68, 6416-6424
   Abstract »    Full Text »    PDF »
Determinants of MicroRNA Processing Inhibition by the Developmentally Regulated RNA-binding Protein Lin28.
E. Piskounova, S. R. Viswanathan, M. Janas, R. J. LaPierre, G. Q. Daley, P. Sliz, and R. I. Gregory (2008)
J. Biol. Chem. 283, 21310-21314
   Abstract »    Full Text »    PDF »
Primary microRNA transcript retention at sites of transcription leads to enhanced microRNA production.
J. M. Pawlicki and J. A. Steitz (2008)
J. Cell Biol. 182, 61-76
   Abstract »    Full Text »    PDF »
Inducible expression of microRNA-194 is regulated by HNF-1{alpha} during intestinal epithelial cell differentiation.
K. Hino, K. Tsuchiya, T. Fukao, K. Kiga, R. Okamoto, T. Kanai, and M. Watanabe (2008)
RNA 14, 1433-1442
   Abstract »    Full Text »    PDF »
Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer.
L. Zhang, S. Volinia, T. Bonome, G. A. Calin, J. Greshock, N. Yang, C.-G. Liu, A. Giannakakis, P. Alexiou, K. Hasegawa, et al. (2008)
PNAS 105, 7004-7009
   Abstract »    Full Text »    PDF »
Epithelial Progenitor Cells of the Embryonic Lung and the Role of MicroRNAs in Their Proliferation.
Y. Lu, T. Okubo, E. Rawlins, and B. L. M. Hogan (2008)
Proceedings of the ATS 5, 300-304
   Abstract »    Full Text »    PDF »
Selective Blockade of MicroRNA Processing by Lin28.
S. R. Viswanathan, G. Q. Daley, and R. I. Gregory (2008)
Science 320, 97-100
   Abstract »    Full Text »    PDF »
Exploration of Tumor-Suppressive MicroRNAs Silenced by DNA Hypermethylation in Oral Cancer.
K.-i. Kozaki, I. Imoto, S. Mogi, K. Omura, and J. Inazawa (2008)
Cancer Res. 68, 2094-2105
   Abstract »    Full Text »    PDF »
Gene Regulation by Transcription Factors and MicroRNAs.
O. Hobert (2008)
Science 319, 1785-1786
   Abstract »    Full Text »    PDF »
MicroRNA-137 Targets Microphthalmia-Associated Transcription Factor in Melanoma Cell Lines.
L. T. Bemis, R. Chen, C. M. Amato, E. H. Classen, S. E. Robinson, D. G. Coffey, P. F. Erickson, Y. G. Shellman, and W. A. Robinson (2008)
Cancer Res. 68, 1362-1368
   Abstract »    Full Text »    PDF »
Development of a Dual-Luciferase Reporter System for In Vivo Visualization of MicroRNA Biogenesis and Posttranscriptional Regulation.
J. Y. Lee, S. Kim, D. W. Hwang, J. M. Jeong, J.-K. Chung, M. C. Lee, and D. S. Lee (2008)
J. Nucl. Med. 49, 285-294
   Abstract »    Full Text »    PDF »
Systematic evaluation of microRNA processing patterns in tissues, cell lines, and tumors.
E. J. Lee, M. Baek, Y. Gusev, D. J. Brackett, G. J. Nuovo, and T. D. Schmittgen (2008)
RNA 14, 35-42
   Abstract »    Full Text »    PDF »
MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression.
D. Y. Lee, Z. Deng, C.-H. Wang, and B. B. Yang (2007)
PNAS 104, 20350-20355
   Abstract »    Full Text »    PDF »
MicroRNAs as Potential Agents to Alter Resistance to Cytotoxic Anticancer Therapy.
J. B. Weidhaas, I. Babar, S. M. Nallur, P. Trang, S. Roush, M. Boehm, E. Gillespie, and F. J. Slack (2007)
Cancer Res. 67, 11111-11116
   Abstract »    Full Text »    PDF »
A simple array platform for microRNA analysis and its application in mouse tissues.
X. Tang, J. Gal, X. Zhuang, W. Wang, H. Zhu, and G. Tang (2007)
RNA 13, 1803-1822
   Abstract »    Full Text »    PDF »
MicroRNA-34b and MicroRNA-34c Are Targets of p53 and Cooperate in Control of Cell Proliferation and Adhesion-Independent Growth.
D. C. Corney, A. Flesken-Nikitin, A. K. Godwin, W. Wang, and A. Yu. Nikitin (2007)
Cancer Res. 67, 8433-8438
   Abstract »    Full Text »    PDF »
MicroRNAs in Tumorigenesis: A Primer.
W. Zhang, J. E. Dahlberg, and W. Tam (2007)
Am. J. Pathol. 171, 728-738
   Abstract »    Full Text »    PDF »
GeneHub-GEPIS: digital expression profiling for normal and cancer tissues based on an integrated gene database.
Y. Zhang, S.-M. Luoh, L. S. Hon, R. Baertsch, W. I. Wood, and Z. Zhang (2007)
Nucleic Acids Res. 35, W152-W158
   Abstract »    Full Text »    PDF »
MicroRNA Expression Profiling in Prostate Cancer.
K. P. Porkka, M. J. Pfeiffer, K. K. Waltering, R. L. Vessella, T. L.J. Tammela, and T. Visakorpi (2007)
Cancer Res. 67, 6130-6135
   Abstract »    Full Text »    PDF »
Oncogenic All1 fusion proteins target Drosha-mediated microRNA processing.
T. Nakamura, E. Canaani, and C. M. Croce (2007)
PNAS 104, 10980-10985
   Abstract »    Full Text »    PDF »
Oncogenic Potential of the miR-106-363 Cluster and Its Implication in Human T-Cell Leukemia.
S. Landais, S. Landry, P. Legault, and E. Rassart (2007)
Cancer Res. 67, 5699-5707
   Abstract »    Full Text »    PDF »
Micromanagement During the Innate Immune Response.
J. E. Dahlberg and E. Lund (2007)
Sci. STKE 2007, pe25
   Abstract »    Full Text »    PDF »
Expression of the miR-17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells.
L. Venturini, K. Battmer, M. Castoldi, B. Schultheis, A. Hochhaus, M. U. Muckenthaler, A. Ganser, M. Eder, and M. Scherr (2007)
Blood 109, 4399-4405
   Abstract »    Full Text »    PDF »
Epigenetic gene silencing in cancer: the DNA hypermethylome.
M. Esteller (2007)
Hum. Mol. Genet. 16, R50-R59
   Abstract »    Full Text »    PDF »
miRNAs in cancer: approaches, aetiology, diagnostics and therapy.
C. Blenkiron and E. A. Miska (2007)
Hum. Mol. Genet. 16, R106-R113
   Abstract »    Full Text »    PDF »
Transcripts Targeted by the MicroRNA-16 Family Cooperatively Regulate Cell Cycle Progression.
P. S. Linsley, J. Schelter, J. Burchard, M. Kibukawa, M. M. Martin, S. R. Bartz, J. M. Johnson, J. M. Cummins, C. K. Raymond, H. Dai, et al. (2007)
Mol. Cell. Biol. 27, 2240-2252
   Abstract »    Full Text »    PDF »
The imprinted H19 noncoding RNA is a primary microRNA precursor.
X. Cai and B. R. Cullen (2007)
RNA 13, 313-316
   Abstract »    Full Text »    PDF »
Overexpression of Dicer in Precursor Lesions of Lung Adenocarcinoma.
S. Chiosea, E. Jelezcova, U. Chandran, J. Luo, G. Mantha, R. W. Sobol, and S. Dacic (2007)
Cancer Res. 67, 2345-2350
   Abstract »    Full Text »    PDF »
Genetic Unmasking of an Epigenetically Silenced microRNA in Human Cancer Cells.
A. Lujambio, S. Ropero, E. Ballestar, M. F. Fraga, C. Cerrato, F. Setien, S. Casado, A. Suarez-Gauthier, M. Sanchez-Cespedes, A. Gitt, et al. (2007)
Cancer Res. 67, 1424-1429
   Abstract »    Full Text »    PDF »
Misexpression of the Caenorhabditis elegans miRNA let-7 Is Sufficient to Drive Developmental Programs.
G.D. HAYES and G. RUVKUN (2006)
Cold Spring Harb Symp Quant Biol 71, 21-27
   Abstract »    PDF »
Drosha in Primary MicroRNA Processing.
Y. LEE, J. HAN, K.-H. YEOM, H. JIN, and V.N. KIM (2006)
Cold Spring Harb Symp Quant Biol 71, 51-57
   Abstract »    PDF »
Substrate Selectivity of Exportin 5 and Dicer in the Biogenesis of MicroRNAs.
E. LUND and J.E. DAHLBERG (2006)
Cold Spring Harb Symp Quant Biol 71, 59-66
   Abstract »    PDF »
The Expanding Universe of Noncoding RNAs.
G.J. HANNON, F.V. RIVAS, E.P. MURCHISON, and J.A. STEITZ (2006)
Cold Spring Harb Symp Quant Biol 71, 551-564
   Abstract »    PDF »

ADVERTISEMENT
Click Me!

ADVERTISEMENT
Click Me!

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (pre-2008: Science's STKE. ISSN 1525-8882)