Mirnas Were Discovered in 1993 By, Rosalind Lee and Rhonda Feinbaum During A Study of The Gene Lin

MicroRNA(miRNA) is a non-coding RNAs that play key roles in the regulation of gene
expression. This class of RNA is recently discovered. miRNAs were discovered in 1993
by Victor Ambros, Rosalind Lee and Rhonda Feinbaum during a study of the gene lin14 in C. elegans development. MicroRNA acts at the post-transcriptional level which
facilitate fine-tune the expression of about 30% of all mammalian protein-encoding
genes. Mature miRNAs are short, single-stranded RNA molecules approximately 22
nucleotides in length. MicroRNAs are sometimes encoded by multiple loci, some of
which are organized in tandemly co-transcribed clusters.
MicroRNA genes are transcribed by RNA polymerase II as large primary transcripts (primiRNA) that are processed by a protein complex containing the RNase III enzyme
Drosha, to form an approximately 70 nucleotide precursor miRNA (pre-miRNA). This
precursor is subsequently transported to the cytoplasm where it is processed by a
second RNase III enzyme, DICER, to form a mature miRNA of approximately 22
nucleotides. The mature microRNA is then incorporated into a ribonuclear particle to
form the RNA-induced silencing complex, RISC, which mediates gene silencing.
There are a lot of functional studies that indicate that miRNA participates in the
regulation of most cellular process and changes in their expression of these miRNA do
characterize several human diseases, including cancer. miRNAs constitute for about 3%
to 5% of predicted genes in the human genome and are estimated to regulate onefourth of protein-coding genes. There are continuous evidences that prove miRNAs can
work as oncogenes by activating the malignant potential of cells as well as act as tumor
suppressor genes by blocking this potential. However, a specific miRNAs can regulate
different targets in different tissues, describing and classifying them as tumor
suppressors or oncogenes before specifying the tissue of their action is not right.(add
Reliv)
MicroRNAs recognize their targets based on sequence complementarity. The mature
miRNA is partially complementary to one or more messenger RNAs. In humans, the
complementary sites are usually within the 3-untranslated region of the target
messenger RNA. To become effective, the mature miRNA forms a complex with
proteins, termed the RNA-induced silencing complex. The miRNA incorporated into the
silencing complex can bind to the target messenger RNA by base pairing. This base
pairing subsequently causes inhibition of protein translation and/or degradation of the
messenger RNA.
Cancer is the disease caused by an uncontrolled division of abnormal cells in a part of
the body. Cancer in human has a multifactorial etiology, with genetic, biological,
physical, and/or chemical agents involved in triggering disease. When discussing
cancer from genetic perspective it can be said that changes that are both qualitative and
quantitative in nature occur in genes that alter the regulation of cell growth,
differentiation, and proliferation leading to transformation.
One of the first lines of evidence that supported that miRNAs can act as oncogenes or
tumor suppressors came from the discovery of the role of miR-16-1 and miR-15a in
chronic lymphocytic leukaemia (CLL), as presented by Carlo M Croce (Human Cancer
Genetics Program, The Ohio State University Medical Center, Columbus, OH, USA).
During attempts to clone a tumor suppressor gene at 13q14, a chromosomal region that
is frequently lost in CLL, the CLL suppressor gene was found to be located in a small
genomic region in which there are no protein-coding genes. However, two miRNA
genes, miR-15a and miR-16-1, are located within this region. This indicates that miR15aand miR-16-1 can function as tumor suppressors and that their loss is associated
with the development of the indolent form of CLL. Following this discovery, Croce and
colleagues mapped the chromosomal locations of other known miRNAs, and
surprisingly, they found that many miRNA genes are located within regions that are
frequently altered in many types of human cancer. In the case of miR-16-1 and miR15a in CLL, the two miRNAs act as tumor suppressors by suppressing expression
of BCL2, an oncogene that inhibits apoptosis and whose overexpression appears to be
a crucial event during the initiation of most forms of the disease.
With further research scientists found a cluster of six miRNAs, the mir-17-92 cluster
which was located within a region on chromosome 13 which is found to be very
commonly amplified in human B-cell lymphomas. In their research He et al.,2005
demonstrated that the miRNAs from the mir-17-92 cluster were overexpressed in
lymphoma cell lines which carry the amplification and that the expression levels
correlated with gene copy number of the mir-17-92 locus. Also it was found that the
miR-17-92 primary transcript was overexpressed in tumor samples from lymphoma
patients. He et al., 2005 to test their hypothesis that mir-17-92actively contributes to
lymphomagenesis used a mouse model of human B-cell lymphoma. These mice
develop lymphomas due to an overexpression of the Myc oncogene. The Myc
oncogene encodes the transcription factor c-Myc that regulates cell proliferation,
growth, and apoptosis, and overexpression of c-Myc is common in cancer. He et al.
demonstrated that additional expression of the mir-17-92 cluster accelerated c-Myc-
induced tumorigenesis in mice. He et al., 2005 therefore concluded that mir-17-92 was
the first potential non-coding oncogene, referred to as oncomir-1.
In the year 2005 ODonnell et al.in their research identified that the cluster of
miRNAs, mir-17-92 was regulated by the transcription factor c-Myc. The transcription
factor Myc induces expression of E2F1 growth factor. The mir-17-92 cluster which is
induced by c-Myc does on the contrary inhibit E2F1 expression. This finding helped
author to reach a conclusion that regulatory mechanism by which c-Myc fine-tunes gene
expression by activating the transcription of target genes and by simultaneously
inducing inhibitory miRNAs that reduce their translation.
The let-7 family of miRNAs was the first group of miRNAs shown to regulate expression of a
proto-oncogene, the RAS protein. RAS proteins are membrane-associated signaling proteins that
regulate cell growth and differentiation. A miRNA that controls expression of these potentially
oncogenic proteins would be predicted to possess tumor suppressor activity.
A microRNA polycistron as a potential human oncogene

He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C,
Lowe SW, Hannon GJ, Hammond SM
Nature. 2005 Jun 9; 435(7043):828-33.
c-Myc-regulated microRNAs modulate E2F1 expression.
O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT
Nature. 2005 Jun 9; 435(7043):839-43.

Mirnas Were Discovered in 1993 By, Rosalind Lee and Rhonda Feinbaum During A Study of The Gene Lin

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MicroRNA(miRNA) is a non-coding RNAs that play key roles in the regulation of gene

A microRNA polycistron as a potential human oncogene

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