An E2F/miR-20a Autoregulatory Feedback Loop

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A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.

Full frame distilled prediction

Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.

Candidate categories

none

Consensus categories

none

Domain

Candidate signal: noneConsensus signal: none

Study design

Candidate signal: Bench or experimentalConsensus signal: Bench or experimental

Genre

Candidate signal: EmpiricalConsensus signal: Empirical

Teacher disagreement score

0.063

Threshold uncertainty score

0.577

Validation status

machine_predicted_unvalidated · codex-gemma-dda1882f352a

Codex and Gemma teacher scores by category

Machine scores (provisional)

The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.

Teacher spread

0.233 · how far apart the two teachers sit on this one work

Validation status

score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it

Abstract

The E2F family of transcription factors is essential in the regulation of the cell cycle and apoptosis. While the activity of E2F1–3 is tightly controlled by the retinoblastoma family of proteins, the expression of these factors is also regulated at the level of transcription, post-translational modifications and protein stability. Recently, a new level of regulation of E2Fs has been identified, where micro-RNAs (miRNAs) from the mir-17–92 cluster influence the translation of the E2F1 mRNA. We now report that miR-20a, a member of the mir-17–92 cluster, modulates the translation of the E2F2 and E2F3 mRNAs via binding sites in their 3′-untranslated region. We also found that the endogenous E2F1, E2F2, and E2F3 directly bind the promoter of the mir-17–92 cluster activating its transcription, suggesting an autoregulatory feedback loop between E2F factors and miRNAs from the mir-17–92 cluster. Our data also point toward an anti-apoptotic role for miR-20a, since overexpression of this miRNA decreased apoptosis in a prostate cancer cell line, while inhibition of miR-20a by an antisense oligonucleotide resulted in increased cell death after doxorubicin treatment. This anti-apoptotic role of miR-20a may explain some of the oncogenic capacities of the mir-17–92 cluster. Altogether, these results suggest that the autoregulation between E2F1–3 and miR-20a is important for preventing an abnormal accumulation of E2F1–3 and may play a role in the regulation of cellular proliferation and apoptosis. The E2F family of transcription factors is essential in the regulation of the cell cycle and apoptosis. While the activity of E2F1–3 is tightly controlled by the retinoblastoma family of proteins, the expression of these factors is also regulated at the level of transcription, post-translational modifications and protein stability. Recently, a new level of regulation of E2Fs has been identified, where micro-RNAs (miRNAs) from the mir-17–92 cluster influence the translation of the E2F1 mRNA. We now report that miR-20a, a member of the mir-17–92 cluster, modulates the translation of the E2F2 and E2F3 mRNAs via binding sites in their 3′-untranslated region. We also found that the endogenous E2F1, E2F2, and E2F3 directly bind the promoter of the mir-17–92 cluster activating its transcription, suggesting an autoregulatory feedback loop between E2F factors and miRNAs from the mir-17–92 cluster. Our data also point toward an anti-apoptotic role for miR-20a, since overexpression of this miRNA decreased apoptosis in a prostate cancer cell line, while inhibition of miR-20a by an antisense oligonucleotide resulted in increased cell death after doxorubicin treatment. This anti-apoptotic role of miR-20a may explain some of the oncogenic capacities of the mir-17–92 cluster. Altogether, these results suggest that the autoregulation between E2F1–3 and miR-20a is important for preventing an abnormal accumulation of E2F1–3 and may play a role in the regulation of cellular proliferation and apoptosis. The proper regulation of cellular proliferation and cell cycle progression is critical for the normal development of organisms and the prevention of cancer. Among the numerous factors involved in these processes, the E2F transcription factors play an essential role (1DeGregori J. Biochim. Biophys. Acta. 2002; 1602: 131-150PubMed Google Scholar, 2Attwooll C. Lazzerini Denchi E. Helin K. EMBO J. 2004; 23: 4709-4716Crossref PubMed Scopus (419) Google Scholar, 3Dyson N. Genes Dev. 1998; 12: 2245-2262Crossref PubMed Scopus (1971) Google Scholar). E2F1, along with E2F2 and E2F3, are activators of cell cycle progression and promote the entry of quiescent cells into S phase (4DeGregori J. Leone G. Miron A. Jakoi L. Nevins J.R. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 7245-7250Crossref PubMed Scopus (607) Google Scholar, 5Johnson D.G. Schwarz J.K. Cress W.D. Nevins J.R. Nature. 1993; 365: 349-352Crossref PubMed Scopus (834) Google Scholar). During G1, E2F1–3 are inhibited by their association with members of the retinoblastoma protein family (pRb, 5The abbreviations used are: Rb, retinoblastoma; miRNA, micro-RNA; UTR, untranslated region; ASO, antisense oligoribonucleotides; FACS, fluorescence-activated cell sorter; PBS, phosphate-buffered saline; GFP, green fluorescent protein; ER, estrogen receptor. p107, and p130) (3Dyson N. Genes Dev. 1998; 12: 2245-2262Crossref PubMed Scopus (1971) Google Scholar). In mid to late G1, hyperphosphorylation of pRb by the cyclinD/cdk4-cdk6 complexes leads to the release of E2F1–3, which bind to specific E2F-responsive promoters, stimulating the transcription of genes involved in G1/S progression (6Stevaux O. Dyson N.J. Curr. Opin. Cell Biol. 2002; 14: 684-691Crossref PubMed Scopus (350) Google Scholar, 7Muller H. Bracken A.P. Vernell R. Moroni M.C. Christians F. Grassilli E. Prosperini E. Vigo E. Oliner J.D. Helin K. Genes Dev. 2001; 15: 267-285Crossref PubMed Scopus (630) Google Scholar). Most cancer cells contain mutations that deregulate the pRb/E2F pathway, which highlights its importance in the control of cellular proliferation. Deregulation of Rb/E2F control can also result in the activation of E2F1-induced apoptosis. Indeed, inactivation of pRb or overexpression of E2F1 promote apoptosis in several cell lines. E2F3 has also been shown to stimulate apoptosis but in a E2F1-dependent pathway (8Lazzerini Denchi E. Helin K. EMBO Rep. 2005; 6: 661-668Crossref PubMed Scopus (99) Google Scholar). E2F1-responsive sites have been found in the promoters of several caspases as well as in other pro-apoptotic targets of p53 (9Nahle Z. Polakoff J. Davuluri R.V. McCurrach M.E. Jacobson M.D. Narita M. Zhang M.Q. Lazebnik Y. Bar-Sagi D. Lowe S.W. Nat. Cell Biol. 2002; 4: 859-864Crossref PubMed Scopus (364) Google Scholar, 10Furukawa Y. Nishimura N. Furukawa Y. Satoh M. Endo H. Iwase S. Yamada H. Matsuda M. Kano Y. Nakamura M. J. Biol. Chem. 2002; 277: 39760-39768Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). E2F1 is also activated by the DNA damage signaling pathway (ATM/ATR) leading to the activation of both p53-dependent and independent, pro-apoptotic pathways (11Urist M. Tanaka T. Poyurovsky M.V. Prives C. Genes Dev. 2004; 18: 3041-3054Crossref PubMed Scopus (195) Google Scholar, 12Lin W.-C. Lin F.-T. Nevins J.R. Genes Dev. 2001; 15: 1833-1844PubMed Google Scholar). Therefore, E2F1 provides direct coupling of the cell cycle and apoptotic machinery, and it has been suggested that cycling cells are primed for apoptosis by E2F1 should proliferation be perceived as aberrant (9Nahle Z. Polakoff J. Davuluri R.V. McCurrach M.E. Jacobson M.D. Narita M. Zhang M.Q. Lazebnik Y. Bar-Sagi D. Lowe S.W. Nat. Cell Biol. 2002; 4: 859-864Crossref PubMed Scopus (364) Google Scholar). Besides the control of their activity by association with pRb, E2F1–3 are also regulated by phosphorylation (13Krek W. Ewen M.E. Shirodkar S. Arany Z. Kaelin J.W.G. Livingston D.M. Cell. 1994; 78: 161-172Abstract Full Text PDF PubMed Scopus (413) Google Scholar), acetylation (14Martinez-Balbas M.A. Bauer U.-M. Nielsen S.J. Brehm A. Kouzarides T. EMBO J. 2000; 19: 662-671Crossref PubMed Scopus (568) Google Scholar, 15Marzio G. Wagener C. Gutierrez M.I. Cartwright P. Helin K. Giacca M. J. Biol. Chem. 2000; 275: 10887-10892Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar), and ubiquitin-dependent degradation (16Campanero M.R. Flemington E.K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2221-2226Crossref PubMed Scopus (183) Google Scholar). E2F1–3 also regulate their own transcription through E2F-binding sites within their promoters (17Johnson D.G. Ohtani K. Nevins J.R. Genes Dev. 1994; 8: 1514-1525Crossref PubMed Scopus (453) Google Scholar, 18Hsiao K.M. McMahon S.L. Farnham P.J. Genes Dev. 1994; 8: 1526-1537Crossref PubMed Scopus (221) Google Scholar). Recently, a novel mechanism of regulation of E2F1 activity has been identified: micro-RNAs (miRNAs) have been found to be important modulators of E2F1 mRNA translation (19O'Donnell K.A. Wentzel E.A. Zeller K.I. Dang C.V. Mendell J.T. Nature. 2005; 435: 839-843Crossref PubMed Scopus (2467) Google Scholar). miRNAs are small 21–23 nucleotides non-coding RNAs that control the stability and/or translation of specific transcripts through the recruitment of the RNA-inducing silencing complex (reviewed in Ref. 20Zamore P.D. Haley B. Science. 2005; 309: 1519-1524Crossref PubMed Scopus (1130) Google Scholar). Recent evidence suggests that miRNAs can regulate the expression of numerous genes (21Lewis B.P. Burge C.B. Bartel D.P. Cell. 2005; 120: 15-20Abstract Full Text Full Text PDF PubMed Scopus (9882) Google Scholar) and several studies point to the role of some miRNAs in the development of cancer (reviewed in Ref. 22Esquela-Kerscher A. Slack F.J. Nat. Rev. Cancer. 2006; 6: 259-269Crossref PubMed Scopus (6202) Google Scholar). Among them, miRNAs from the mir-17–92 cluster have been shown to have an oncogenic activity when overexpressed with c-myc in a mouse model of human B-cell lymphoma (23He L. Thomson J.M. Hemann M.T. Hernando-Monge E. Mu D. Goodson S. Powers S. Cordon-Cardo C. Lowe S.W. Hannon G.J. Hammond S.M. Nature. 2005; 435: 828-833Crossref PubMed Scopus (3146) Google Scholar). Interestingly, this cluster is amplified in large-B cell lymphoma and in other malignant lymphomas (24Ota A. Tagawa H. Karnan S. Tsuzuki S. Karpas A. Kira S. Yoshida Y. Seto M. Cancer Res. 2004; 64: 3087-3095Crossref PubMed Scopus (631) Google Scholar). Moreover, miRNAs from this cluster are overexpressed in lung cancer cells and in colon, pancreas, and prostate tumors (25Hayashita Y. Osada H. Tatematsu Y. Yamada H. Yanagisawa K. Tomida S. Yatabe Y. Kawahara K. Sekido Y. Takahashi T. Cancer Res. 2005; 65: 9628-9632Crossref PubMed Scopus (1381) Google Scholar, 26Volinia S. Calin G.A. Liu C.-G. Ambs S. Cimmino A. Petrocca F. Visone R. Iorio M. Roldo C. Ferracin M. Prueitt R.L. Yanaihara N. Lanza G. Scarpa A. Vecchione A. Negrini M. Harris C.C. Croce C.M. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 2257-2261Crossref PubMed Scopus (4963) Google Scholar). Another group has also shown that the mir-17–92 cluster is directly regulated by MYC, and two miRNAs from this cluster, miR-17a and miR-20a, inhibited the translation of the E2F1 mRNA (19O'Donnell K.A. Wentzel E.A. Zeller K.I. Dang C.V. Mendell J.T. Nature. 2005; 435: 839-843Crossref PubMed Scopus (2467) Google Scholar). Altogether, these results suggest that miRNAs from the mir-17–92 cluster can act as oncogenic miRNAs or “oncomirs” when overexpressed, possibly by acting on key regulators of the cell cycle and apoptosis, like E2F1. Here, we that miR-20a, a member of the mir-17–92 cluster, E2F1 but also E2F2 and E2F3 via binding sites in the of their We also report that E2F1–3 directly bind the promoter of the mir-17–92 cluster its While overexpression of miR-20a decreased apoptosis in a prostate cancer cell line, inhibition of miR-20a by an antisense oligonucleotide resulted in increased cell death after doxorubicin to a anti-apoptotic role for Altogether, these results suggest that the autoregulation between E2F1–3 and miR-20a is important for a between E2F in cellular proliferation and apoptosis. E2Fs amplified from the DNA of cells the E2F1, and E2F2, and E2F3, The and of E2F1, E2F2, and E2F3 into the of the the the to the of the miR-20a miRNA in by the the promoter a of from the cluster promoter E2F-binding sites amplified from DNA the and The between the and sites of the miR-20a, we the miRNA after from human DNA with the and The into the and cells at cells well in a The the or with the of the cluster the a of the promoter into cells at cells in in with or with of of a protein and The of at by the to the of The after for activity the of E2Fs of into cells cells well in with the the promoter the the promoter or the the of E2F1 with the antisense used in this miR-20a and The by DNA the at in after activity to activity for the on to a a and the in the The to and at and the for Cell cells at cells well in a The after the and doxorubicin after and with to the cell death The in miR-20a or in cells and with cells well in a from of the in with or doxorubicin cells and with of cells the of Cell or into cells cells well directly into with or doxorubicin and cells to for with and with in with several with of and which is to cell with of and of used for at in with a the of and in the cell cells well directly into with or doxorubicin and cells to for with with and the of cells and with PBS, and the in of and on for and the for The with of with PBS, two with and in and at The on a and to The used for mouse mouse after with to by of E2F1–3 by E2F1 expression regulated by factors binding to its we the of E2F1 to a We a in activity from cells when with a to the of (19O'Donnell K.A. Wentzel E.A. Zeller K.I. Dang C.V. Mendell J.T. Nature. 2005; 435: 839-843Crossref PubMed Scopus (2467) Google Scholar) that the E2F1 mRNA binding sites for miRNAs that regulated its we the two sites in the E2F1 mRNA both sites we an in activity to the control level Moreover, of the with miR-20a resulted in a in activity with a control these data the that the translation of the E2F1 mRNA is regulated by miRNAs from the mir-17–92 cluster, miR-20a, through sites in the E2F1 mRNA (19O'Donnell K.A. Wentzel E.A. Zeller K.I. Dang C.V. Mendell J.T. Nature. 2005; 435: 839-843Crossref PubMed Scopus (2467) Google Scholar). it is that other members of the E2F E2F2 and E2F3, of like and activation (3Dyson N. Genes Dev. 1998; 12: 2245-2262Crossref PubMed Scopus (1971) Google Scholar, 15Marzio G. Wagener C. Gutierrez M.I. Cartwright P. Helin K. Giacca M. J. Biol. Chem. 2000; 275: 10887-10892Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, D.G. Ohtani K. Nevins J.R. Genes Dev. 1994; 8: 1514-1525Crossref PubMed Scopus (453) Google Scholar), we the that miR-20a also regulate the translation of the E2F2 and E2F3 mRNAs via binding sites in their Indeed, the of sites in the of the E2F2 mRNA and in the of the E2F3 mRNA B. A. T. C. Biol. 2004; PubMed Scopus Google Scholar) at the of the in the control and in cells to its the E2F2 that the two with the control in activity from the and the we have for the E2F1 we the binding sites of miR-20a in the and E2F3 shown in of the miR-20a sites increased activity in both mRNAs the level of the suggesting that binding of miR-20a in these We also the of miR-20a on the expression of endogenous shown in of cells with the miR-20a resulted in an increased level of E2F1 and E2F2, as by with we have been to E2F3 member of the miR-20a also increased both E2F1 and E2F2 with the control Altogether, these results suggest that like E2F1, the E2F2 and E2F3 mRNAs are also targets of of endogenous of E2F1 and E2F2 in cells with miR-20a, or to with of by E2F1–3 are transcription we the that may regulate the expression of the miR-20a We cells estrogen of E2F1, E2F2, and E2F3 E. H. Prosperini E. G. Cartwright P. Moroni M.C. Helin K. Cell Biol. 19: PubMed Scopus Google Scholar). of from these cells and the level of miR-20a by shown in overexpression of E2F1–3 to an increased level of miR-20a with the control suggesting that the E2F1, E2F2, and E2F3 transcription factors can the expression of We also cells with a of a which the but the Interestingly, of this E2F also to increased miR-20a studies have of the in cellular C. Lazzerini Denchi E. Helin K. EMBO J. 2004; 23: 4709-4716Crossref PubMed Scopus (419) Google Scholar), which suggests that the of a complex from a promoter by the may be to The miR-20a miRNA is of a cluster of the mir-17–92 cluster, which is on the (24Ota A. Tagawa H. Karnan S. Tsuzuki S. Karpas A. Kira S. Yoshida Y. Seto M. Cancer Res. 2004; 64: 3087-3095Crossref PubMed Scopus (631) Google Scholar). This cluster has been shown to be by the (19O'Donnell K.A. Wentzel E.A. Zeller K.I. Dang C.V. Mendell J.T. Nature. 2005; 435: 839-843Crossref PubMed Scopus (2467) Google Scholar) and amplified in lymphomas (23He L. Thomson J.M. Hemann M.T. Hernando-Monge E. Mu D. Goodson S. Powers S. Cordon-Cardo C. Lowe S.W. Hannon G.J. Hammond S.M. Nature. 2005; 435: 828-833Crossref PubMed Scopus (3146) Google Scholar). the increased expression of miR-20a at the level of the mir-17–92 cluster we of a cell We used to the level of of shown in of the resulted in an increased suggesting that the cluster is by this cluster may be directly regulated by the E2F1–3 transcription we for E2F-binding sites within the of the promoter of the mir-17–92 cluster E2Fs are to bind to a S in the promoters of their genes Y. Cress W.D. J.M. Cell Biol. 1997; PubMed Scopus Google Scholar). We E2F-binding sites in the mir-17–92 promoter to this and the binding of these E2Fs to the we to the association of the endogenous E2F1, E2F2, and E2F3 transcription factors with the mir-17–92 promoter in cells In the mir-17–92 we which is to two E2F-binding sites and which two other E2F-binding sites and and which the sites (19O'Donnell K.A. Wentzel E.A. Zeller K.I. Dang C.V. Mendell J.T. Nature. 2005; 435: 839-843Crossref PubMed Scopus (2467) Google Scholar). used as a while E2F1 in the E2F1 promoter used as a shown in and amplified after with and E2F3 but with an the amplified with the and Interestingly, a of the with E2F3 with E2F2 or E2F1. may that E2F3 to this of the promoter or that the E2F3 is for that the mir-17–92 cluster is regulated by the we a of this the E2F-binding sites the and of the in the of this with of the resulted in an increased activation of the E2F1 a activation of this promoter by E2F3 E2F2 activation While E2F2 as as E2F1 and E2F3 to miR-20a it may bind to sites that are of the in the of an E2F in the results that this of the mir-17–92 cluster promoter is to the E2F1–3 transcription Altogether, these data suggest a where the translation of the E2F1–3 mRNAs is controlled by the miR-20a miRNA, which is regulated by the E2Fs at the of the of E2F1–3 by an of E2F1–3 miR-20a should expression and may act as an and/or as an anti-apoptotic these we the of the of miR-20a on the activity of endogenous we cells with genes the control of the or both promoters K. J. Leone G. Nevins J.R. Cell. Biol. PubMed Scopus Google Scholar, T. Nat. 2000; PubMed Scopus Google Scholar). The cells with a the endogenous miR-20a shown in inhibition of miR-20a resulted in a in the activation of the promoter and promoter control the miRNA result in the of these with the increased E2F1–3 expression when cells with the miR-20a and suggests an increased E2F1–3 activity in these the of an increased or decreased miR-20a we of a prostate cancer cell that used to apoptosis after with the DNA damage doxorubicin G. Cancer Res. 2005; 65: PubMed Scopus Google Scholar). In these an increased E2F activity with apoptosis after with doxorubicin G. Cancer Res. 2005; 65: PubMed Scopus Google Scholar). We an endogenous miR-20a activity in cells by a decreased activity from the with the with miR-20a sites the inhibition of miR-20a the level of apoptosis of with the or a and with Cell death by after in shown in of the miR-20a resulted in a in cell death after doxorubicin with the suggesting that inhibition of miR-20a these cells to apoptosis. We also overexpressed the miR-20a miRNA in cells by of a a miR-20a from cells with the an expression of the miR-20a miRNA of miR-20a resulted in a in the endogenous level of E2F1 and E2F2, as shown by The of these cells by the overexpression of miR-20a, suggesting that it may E2F1–3 expression to an to cell cycle after with cells the miR-20a miRNA a in cell death with the control cells cell after doxorubicin with a we a in cell of cells miR-20a with control cells with the We also cell accumulation in after doxorubicin of cells or when miR-20a overexpressed, we cells in to the control cells and suggest an increased level of cell after with a DNA damage when miR-20a is overexpressed in these the that miR-20a has an anti-apoptotic possibly through its regulation of E2F1 cells from cell on miR-20a miRNA from cells with the control or the of the of E2F1 and E2F2 in cells with the control or the to with cell death of cells with or control after with doxorubicin Cell death the of cells with or after with doxorubicin to the with of cells with or after with doxorubicin to the with The of which explain the of cell or their to have been as the of the of regulators that can or specific a family of small has to this of miRNAs can regulate expression both at and P.D. Haley B. Science. 2005; 309: 1519-1524Crossref PubMed Scopus (1130) Google Scholar). has been that can act as or as regulators of Cell. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). miRNAs are by can be regulated by This that can be between genes for transcription factors and genes for We report that the mir-17–92 cluster is directly regulated by the E2F family of transcription several miRNAs in this cluster can E2F1–3 an autoregulatory feedback loop can be between E2Fs and the mir-17–92 cluster is well that E2F1–3 are involved in a autoregulatory loop stimulate their own genes (17Johnson D.G. Ohtani K. Nevins J.R. Genes Dev. 1994; 8: 1514-1525Crossref PubMed Scopus (453) Google Scholar, 18Hsiao K.M. McMahon S.L. Farnham P.J. Genes Dev. 1994; 8: 1526-1537Crossref PubMed Scopus (221) Google Scholar). We that a role of the miR-20a miRNA family is to the autoregulatory loop of E2F1–3 by a feedback loop to control the level of expression of these transcription We suggest that other transcription factors involved in autoregulatory may also be controlled by feedback miRNAs as may be the transcription which is involved in and which is to the transcription of its own S.J. R.L. H. Cell. Full Text PDF PubMed Scopus Google Scholar). Recently, and M. S. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: PubMed Scopus Google Scholar) have shown that the transcription of the specific and Interestingly, the mRNA has a in its (21Lewis B.P. Burge C.B. Bartel D.P. Cell. 2005; 120: 15-20Abstract Full Text Full Text PDF PubMed Scopus (9882) Google Scholar), and it may be involved in a feedback loop that and In the feedback loop between E2F1–3 and miR-20a, of be to the activation of the mir-17–92 cluster by (19O'Donnell K.A. Wentzel E.A. Zeller K.I. Dang C.V. Mendell J.T. Nature. 2005; 435: 839-843Crossref PubMed Scopus (2467) Google Scholar). E2F1–3 are to the transcription of K. H. R. M. Genes Dev. PubMed Scopus Google Scholar), and can the transcription of E2F1–3 G. J. R. Jakoi L. Nevins J.R. Nature. 1997; PubMed Scopus Google Scholar, M.R. R. F. Leone G. Nevins J.R. Cell. Biol. 2000; PubMed Scopus Google Scholar), and both transcription factors the mir-17–92 cluster, it suggest that this may a novel of the loop S. U. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), which can be as a loop of the feedback loop between E2Fs and the miR-20a family of miRNAs be to a mechanism to E2F E2F activity is for the it can to cell death or malignant on the cellular The of this may be to normal cell cycle where E2F1–3 can to the well that E2F1–3 regulate their own This also the that the E2Fs with miR-20a inhibition may from an increased E2Fs mRNA translation but may be in by a of the of the E2F1–3 genes by E2F Our that miR-20a targets the of the E2F1 mRNA with the mRNAs of E2F2 and E2F3 suggest that E2F1 are critical to cell possibly to the of E2F1. This regulation may also be to cell where the family is by hyperphosphorylation and E2F activity is to the cell cycle J. E. R. S. Cartwright P. S. Biol. Cell. 2005; PubMed Scopus Google Scholar). Interestingly, the mir-17–92 cluster is in mouse cells J.M. J. C.M. Hammond S.M. Nat. 2004; PubMed Scopus Google Scholar), which suggests the that in the of E2F1–3 activity may be controlled by this feedback The autoregulatory feedback loop may be also the of normal cells into E2F1 is to have both and oncogenic on the cellular the miRNA mechanism that E2Fs can promote or oncogenic role for the miR-20a family of miRNAs is with the anti-apoptotic role of this miRNA in this expression of the mir-17–92 cluster in a mouse (23He L. Thomson J.M. Hemann M.T. Hernando-Monge E. Mu D. Goodson S. Powers S. Cordon-Cardo C. Lowe S.W. Hannon G.J. Hammond S.M. Nature. 2005; 435: 828-833Crossref PubMed Scopus (3146) Google Scholar). While the anti-apoptotic of miR-20a may explain this oncogenic activity and the in cell death in the mouse the mir-17–92 cluster, a has shown that apoptosis in the mouse is J. E. C. A. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). it is that other members of the mir-17–92 cluster may other In the of miRNAs are and the in where expression is the other in other cell the miR-20a family may act as a by preventing the activity of In the mir-17–92 cluster found in a of and L. J. N. J. A. S. A. M.R. G. A. A. D. A. G. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: PubMed Scopus Google Scholar). Our results to the of the complex pathways E2F activity and are for studies on cell cycle cell and In the between miRNAs and transcription factors may a We of for the and K. Helin for the E2F1–3 expression with

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The record

Venue

Journal of Biological Chemistry

Topic

MicroRNA in disease regulation

Field

Biochemistry, Genetics and Molecular Biology

Canadian institutions

Institute for Research in Immunology and CancerUniversité de Montréal

Funders

not available

Keywords

Control theory (sociology)Feedback loopLoop (graph theory)Negative feedbackComputer sciencePhysicsMathematicsControl (management)Artificial intelligenceVoltageCombinatoricsComputer security

Has abstract in OpenAlex

yes

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