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miR-20a and miR-290, multi-faceted players with a role in tumourigenesis and senescence.

Rizzo M, Mariani L, Pitto L, Rainaldi G, Simili M - J. Cell. Mol. Med. (2010)

Bottom Line: Expression of microRNAs changes markedly in tumours and evidence indicates that they are causatively related to tumourigenesis, behaving as tumour suppressor microRNAs or onco microRNAs; in some cases they can behave as both depending on the type of cancer.The INK4a/ARF locus which codifies for two proteins, p19ARF and p16INK4a, plays a central role in senescence by controlling both p53 and RB.Intriguingly, both miR-20a, member of the oncogenic miR-17-92 cluster, and miR-290, belonging to the miR-290-295 cluster, are highly expressed in embryonic stem (ES) cells.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Gene and Molecular Therapy, Institute of Clinical Physiology, CNR, Pisa, Italy.

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MiR-20: a multifaceted miRNA which affects multiple pathways. (A) MiR-17–92 cluster is part of a self-regulating circuit: schematically cMYC binds the promoter of the cluster as well as that of E2F1 increasing their transcription; in turn E2F1 induces the cluster transcription. MiR-20a, a member of the cluster, directly targets E2F1 in order to control its level. In tumour cells, where E2F1 level is high, miR-20a increases the oncogenic power of cMYC by keeping E2F1 level below the pro-apoptotic threshold (left side). This concept is schematically visualized as a bar which represents the full range of cellular E2F1 level variation; the red rectangles within the bar represent the actual E2F1 quantities which determine the final biological outcome (cell proliferation in the case of tumour cells). On the contrary, in MEF, where E2F1 level is limiting, miR-20a induces cell cycle block and senescence by down-regulating E2F1 below the cell proliferation threshold (right side). Blue lines represent thresholds between the different biological outcome (apoptosis, proliferation and cell cycle block). (B) miR-20a induces senescence by affecting multiple pathways: it down-regulates LRF thereby stabilizing p53 via p19ARF activation, it down-regulates directly E2F1 and indirectly up-regulates p16INK4a. Dashed lines indicate hypothetical pathways.
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fig02: MiR-20: a multifaceted miRNA which affects multiple pathways. (A) MiR-17–92 cluster is part of a self-regulating circuit: schematically cMYC binds the promoter of the cluster as well as that of E2F1 increasing their transcription; in turn E2F1 induces the cluster transcription. MiR-20a, a member of the cluster, directly targets E2F1 in order to control its level. In tumour cells, where E2F1 level is high, miR-20a increases the oncogenic power of cMYC by keeping E2F1 level below the pro-apoptotic threshold (left side). This concept is schematically visualized as a bar which represents the full range of cellular E2F1 level variation; the red rectangles within the bar represent the actual E2F1 quantities which determine the final biological outcome (cell proliferation in the case of tumour cells). On the contrary, in MEF, where E2F1 level is limiting, miR-20a induces cell cycle block and senescence by down-regulating E2F1 below the cell proliferation threshold (right side). Blue lines represent thresholds between the different biological outcome (apoptosis, proliferation and cell cycle block). (B) miR-20a induces senescence by affecting multiple pathways: it down-regulates LRF thereby stabilizing p53 via p19ARF activation, it down-regulates directly E2F1 and indirectly up-regulates p16INK4a. Dashed lines indicate hypothetical pathways.

Mentions: The pro-senescence role of miR-20a [41] appears to be in contrast with its oncogenic role [47]; however a more subtle interpretation of the data highlights a particular aspect of miRNA properties discussed above: i.e. the cellular context may be decisive for the final effect of miRNAs. In tumour cells the miR-17–92 cluster increases the oncogenic power of cMYC in a self-regulating circuit whereby cMYC binds the promoter of the miR-17–92 cluster and increases its transcription [51]. In turn two miRNAs of the cluster, miR-17–5p and miR-20a (belonging to the same seed family), target E2F1, which is able to activate both the cluster and cMYC [52]. In other words, cMYC, while directly increasing the transcription of E2F1, indirectly decreases its translation by inducing miR-17–5p and miR-20a. In this way, cMYC uses the miR-17 seed family to maintain E2F1 protein levels below the pro-apoptotic threshold allowing the proliferative signal to prevail (Fig. 2A, left side) [53]. Conversely in MEF, where E2F1 levels is limiting, its down-regulation by miR-20a contributes to senescence (Fig. 2A, right side) in agreement with the idea that miRNAs might have opposite effects in different cells. In this regard it would be interesting to test miR-20a in tumours where inhibition of E2F1 transcriptional activity has been found to block tumour growth [27, 54].


miR-20a and miR-290, multi-faceted players with a role in tumourigenesis and senescence.

Rizzo M, Mariani L, Pitto L, Rainaldi G, Simili M - J. Cell. Mol. Med. (2010)

MiR-20: a multifaceted miRNA which affects multiple pathways. (A) MiR-17–92 cluster is part of a self-regulating circuit: schematically cMYC binds the promoter of the cluster as well as that of E2F1 increasing their transcription; in turn E2F1 induces the cluster transcription. MiR-20a, a member of the cluster, directly targets E2F1 in order to control its level. In tumour cells, where E2F1 level is high, miR-20a increases the oncogenic power of cMYC by keeping E2F1 level below the pro-apoptotic threshold (left side). This concept is schematically visualized as a bar which represents the full range of cellular E2F1 level variation; the red rectangles within the bar represent the actual E2F1 quantities which determine the final biological outcome (cell proliferation in the case of tumour cells). On the contrary, in MEF, where E2F1 level is limiting, miR-20a induces cell cycle block and senescence by down-regulating E2F1 below the cell proliferation threshold (right side). Blue lines represent thresholds between the different biological outcome (apoptosis, proliferation and cell cycle block). (B) miR-20a induces senescence by affecting multiple pathways: it down-regulates LRF thereby stabilizing p53 via p19ARF activation, it down-regulates directly E2F1 and indirectly up-regulates p16INK4a. Dashed lines indicate hypothetical pathways.
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fig02: MiR-20: a multifaceted miRNA which affects multiple pathways. (A) MiR-17–92 cluster is part of a self-regulating circuit: schematically cMYC binds the promoter of the cluster as well as that of E2F1 increasing their transcription; in turn E2F1 induces the cluster transcription. MiR-20a, a member of the cluster, directly targets E2F1 in order to control its level. In tumour cells, where E2F1 level is high, miR-20a increases the oncogenic power of cMYC by keeping E2F1 level below the pro-apoptotic threshold (left side). This concept is schematically visualized as a bar which represents the full range of cellular E2F1 level variation; the red rectangles within the bar represent the actual E2F1 quantities which determine the final biological outcome (cell proliferation in the case of tumour cells). On the contrary, in MEF, where E2F1 level is limiting, miR-20a induces cell cycle block and senescence by down-regulating E2F1 below the cell proliferation threshold (right side). Blue lines represent thresholds between the different biological outcome (apoptosis, proliferation and cell cycle block). (B) miR-20a induces senescence by affecting multiple pathways: it down-regulates LRF thereby stabilizing p53 via p19ARF activation, it down-regulates directly E2F1 and indirectly up-regulates p16INK4a. Dashed lines indicate hypothetical pathways.
Mentions: The pro-senescence role of miR-20a [41] appears to be in contrast with its oncogenic role [47]; however a more subtle interpretation of the data highlights a particular aspect of miRNA properties discussed above: i.e. the cellular context may be decisive for the final effect of miRNAs. In tumour cells the miR-17–92 cluster increases the oncogenic power of cMYC in a self-regulating circuit whereby cMYC binds the promoter of the miR-17–92 cluster and increases its transcription [51]. In turn two miRNAs of the cluster, miR-17–5p and miR-20a (belonging to the same seed family), target E2F1, which is able to activate both the cluster and cMYC [52]. In other words, cMYC, while directly increasing the transcription of E2F1, indirectly decreases its translation by inducing miR-17–5p and miR-20a. In this way, cMYC uses the miR-17 seed family to maintain E2F1 protein levels below the pro-apoptotic threshold allowing the proliferative signal to prevail (Fig. 2A, left side) [53]. Conversely in MEF, where E2F1 levels is limiting, its down-regulation by miR-20a contributes to senescence (Fig. 2A, right side) in agreement with the idea that miRNAs might have opposite effects in different cells. In this regard it would be interesting to test miR-20a in tumours where inhibition of E2F1 transcriptional activity has been found to block tumour growth [27, 54].

Bottom Line: Expression of microRNAs changes markedly in tumours and evidence indicates that they are causatively related to tumourigenesis, behaving as tumour suppressor microRNAs or onco microRNAs; in some cases they can behave as both depending on the type of cancer.The INK4a/ARF locus which codifies for two proteins, p19ARF and p16INK4a, plays a central role in senescence by controlling both p53 and RB.Intriguingly, both miR-20a, member of the oncogenic miR-17-92 cluster, and miR-290, belonging to the miR-290-295 cluster, are highly expressed in embryonic stem (ES) cells.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Gene and Molecular Therapy, Institute of Clinical Physiology, CNR, Pisa, Italy.

Show MeSH
Related in: MedlinePlus