User:inarus2/L7 pre mirna
let-7 microRNA precursor | |
---|---|
SO | SO:0001244 |
PDB structures | PDBe |
The Let-7 microRNA precursor was identified from a study of developmental timing in
Genomic Locations
In human genome, the cluster let-7a-1/let-7f-1/let-7d is inside the region B at 9q22.3, with the defining marker D9S280-D9S1809. One minimal LOH (loss of heterozygosity) region, between loci D11S1345-D11S1316, contains the cluster miR-125b1/let-7a-2/miR-100. The cluster miR-99a/let-7c/miR-125b-2 is in a 21p11.1 region of HD (homozygous deletions). The cluster let-7g/miR-135-1 is in region 3 at 3p21.1-p21.2.[3]
The let-7 family
The lethal-7 (let-7) gene was first discovered in the nematode as a key developmental regulator and became one of the first two known microRNAs (the other one is lin-4).[4] Soon, let-7 was found in fruit fly, and identified as the first known human miRNA by a BLAST (basic local alignment search tool) research.[5] The mature form of let-7 family members is highly conserved across species.
In C.elegans
In C.elegans, the let-7 family consists of genes encoding nine miRNAs sharing the same seed sequence.[6] Among them, let-7, mir-84, mir-48 and mir-241 are involved in C.elegans heterochronic pathway, sequentially controlling developmental timing of larva transitions.[7] Most animals with loss-of-function let-7 mutation burst through their vulvas and die, and therefore the mutant is lethal (let).[4] The mutants of other let-7 family members have a radio-resistant phenotype in vulval cells, which may be related to their ability to repress RAS.[8]
In Drosophila
There is only one single let-7 gene in the Drosophila genome, which has the identical mature sequence to the one in C.elegans.[9] The role of let-7 has been demonstrated in regulating the timing of neuromuscular junction formation in the abdomen and cell-cycle in the wing.[10] Furthermore, the expression of pri-, pre- and mature let-7 have the same rhythmic pattern with the hormone pulse before each cuticular molt in Drosophila.[11]
In vertebrates
The let-7 family has a lot more members in vertebrates than in C.elegans and Drosophila.[9] And the sequences, expression timing, as well as genomic clustering of these miRNAs members are all conserved across species.[12] The direct role of let-7 family in vertebrate development has not been clearly shown as in less complex organisms, yet the expression pattern of let-7 family is indeed temporal during developmental processes.[13] Given that the expression levels of let-7 members are significantly low in human cancers and cancer stem cells,[14] the major function of let-7 genes may be to promote terminal differentiation in development and tumor suppression.
Regulation of expression
Although the levels of mature let-7 members are undetectable in undifferentiated cells, the primary transcripts and the hairpin precursors of let-7 are present in these cells.[15] It indicates that the mature let-7 miRNAs may be regulated in a post-transcriptional manner.
By pluripotency promoting factor LIN28
As one of the four genes involved in induced pluripotent stem (iPS) cells reprogramming,[16] LIN28 expression is reciprocal to that of mature let-7.[17] LIN28 selectively binds the primary and precursor forms of let-7, and inhibits the processing of pri-let-7 to form the hairpin precursor.[18] This binding is facilitated by the conserved loop sequence of primary let-7 family members and RNA-binding domains of LIN28 proteins.[19] On the other hand, let-7 miRNAs in mammals have been shown to regulate LIN28,[20] which implies that let-7 might enhance its own level by repressing LIN28, its negative regulator.
In autoregulatory loop with MYC
Expression of let-7 members is controlled by
Targets of let-7
Oncogenes: RAS, HMGA2
Let-7 has been demonstrated to be a direct regulator of RAS expression in human cells[24] All the three RAS genes in human, K-, N-, and H-, have the predicted let-7 binding sequences in their 3'UTRs. In lung cancer patient samples, expression of RAS and let-7 showed reciprocal pattern, which has low let-7 and high RAS in cancerous cells, and high let-7 and low RAS in normal cells. Another oncogene, high mobility group A2 (HMGA2), has also been identified as a target of let-7. Let-7 directly inhibits HMGA2 by binding to its 3'UTR.[25] Removal of let-7 binding site by 3'UTR deletion cause overexpression of HMGA2 and formation of tumor. MYC is also considered as a oncogenic target of let-7.
Cell cycle, proliferation, and apoptosis regulators
Immunity
Let-7 has been implicated in post-transcriptional control of
Potential clinical use in cancer
Given the prominent phenotype of cell overproliferation and undifferentiation by let-7 loss-of-function in nematodes, and the role of its targets on cell destiny determination, let-7 is closely associated with human cancer and acts as a tumor suppressor.
Diagnosis
Numerous reports have shown that the expression levels of let-7 are frequently low and the chromosomal clusters of let-7 are often deleted in many cancers.[3] Let-7 is expressed at higher levels in more differentiated tumors, which also have lower levels of activated oncogenes such as RAS and HMGA2. Therefore, expression levels of let-7 could be prognostic markers in several cancers associated with differentiation stages.[35] In lung cancer, for example, reduced expression of let-7 is significantly correlated with reduced postoperative survival.[36]
Therapy
Let-7 is also a very attractive potential therapeutic that can prevent
References
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(help)CS1 maint: multiple names: authors list (link - ^ Barh D., Malhotra R., Ravi B., and Sindhurani P. (2010). MicroRNA let-7: an emerging next-generation cancer therapeutic. CURRENT ONCOLOGY. 17, 70-80.
Further reading
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