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  1. Summary • Non Coding RNA • MiRNA History • miRNA Functions • Mi RNA Pathway • mi RNA role in regulation of teranscription • Data-based Modeling of the JAK-STAT Pathway • Negative Regulation of the JAK-STAT pathwey • Cancers caused by mi- RNA155

  2. MiRNA History • Firstly detected in C. elegans (V. Ambros, 1993) • Regulatory RNAs of 22 nucleotides in length • Found in plants and metazoans • Found in humans: • More than 500 different miRNAs • Expressed in a developmental or tissue specific manner • Between 10–30% of all human genes are a target for microRNA regulation (John et al, 2004; Lewis et al, 2005).

  3. miRNA Functions • microRNAs play key regulatory roles • control of haematopoiesis • developmental timing • cell differentiation • apoptosis • cell proliferation • organ development as well as in cancer, infectious disease, genetic disorders (Lin et al, 2006) and even heart disease (van Rooij et al, 2006)

  4. MiRNAsBiological role • Brain development (miR-430) • • Nervous system development(miR-273) • • Pancreatic Langerhans islands development (miR-375) • • Adipocytes development (miR-143) • • Heart development(miR-1) • Inmune response (miR-223, cluster miR-17~92, miR-146a,miR-155…) • • Apoptosis (miR-14)

  5. Mi RNA Pathway • Mapping to non-coding regions (introns) • Pri-miRNA processed by Drosha • DICER removes the structural loop • mature miRNA: ssRNA, 22 nucleotides • miRNA-RISK complex: mRNAs post-transcriptional inhibition animation

  6. mi RNA Locatation • The majority of human microRNAs are encoded within introns of coding or non-coding mRNAs whilst others are located within the exons of non-coding mRNAs or within the 3’UTR sequence of mRNA (Rodriguez et al, 2004).

  7. mi RNA role in regulation of teranscription • MicroRNAs primarily function as translational repressors by binding to complementary target sequences in the 3’ UTR (untranslated region) of mRNA

  8. miRNAsDetection Methods

  9. Data-based Modeling of the JAK-STAT Pathway • a receptor • Janus Kinase (JAK) • Signal Transducer and Activator of Transcription(STAT)

  10. Structural and Functional Domains of JAK Family JAK family : JAK1, JAK2, JAK3 and TYK2 Nat. Rev. Mol. Cell Biol. 2002 3:651

  11. STATs: Signal Transducers and Activators of Transcription • two functions given in the name • 1. Transducers for signals from many cytokines • Broad spectrum of biological effects • 2. Transcriptional activators • characteristic activation mechanism • activation at the cell membrane, response in the nucleus • Rapid signal response • The activation/deactivation cycle of STAT molecules is quite short, about 15 min for an individual molecule.

  12. Simple signalling pathway

  13. The JAK-STAT signalling pathway • Function: regulation of gene expression in response to cytokines • 1. cytokines bind and aggregate the cytokine receptors in the cell membrane • 2. associated JAK-type tyrosine kinases are activated by aggregation and tyrosine-phosphorylates neighbouring-JAK (transphosphorylation) as well as the C-terminal tail of the receptor (multiple sites) • 3. Tyr-phosphates recruit inactive STAT-factors in the cytoplasm which are bound through their SH2-domains • 4. STATs become tyrosine-phosphorylated by JAK • 5. phosphorylated STATs dissociate, dimerize (homo-/hetero-) and migrate to the nucleus • 6. STAT-dimers bind DNA and activates target genes

  14. Canonical JAK–STAT pathway • Sequential tyrosine phosphorylations • Receptor dimerization allows transphosphorylation and activation of Janus kinases (JAKs). • This is followed by phosphorylation of receptor tails and the recruitment of the STAT proteins through their SH-2 domains. STAT tyrosine phosphorylation then occurs. • Dimerization of activated (tyrosine phosphorylated) STAT is followed by nuclear entry.

  15. Activation of JAKs and STATs by Cytokines Ligand Jak kinases STATs IFN family Type I IFN- IFNa or IFNb Tyk2, Jak1 STAT1, STAT2 Type II IFN-IFNg Jak1, Jak2 STAT1 gC family IL-2 Jak1, Jak3 STAT5 IL-4 Jak1, Jak3 STAT5 IL-7 Jak1, Jak3 STAT5 gp130 family IL-6 Jak2 STAT3 IL-11 Jak2 STAT3 Modified from Gene 2002 285:1

  16. Negative Regulation of the JAK-STAT pathwey • Receptor-mediated endocytosis and degradation • Dephosphorylation by tyrosine phosphatases • Naturally occurring dominant negative STATs such as STAT1b and STAT3b that don’t have transactivating domain • Suppressor of cytokine signaling (SOCS) family • Protein inhibitor of activated Stats (PIAS)

  17. Suppressor Of Cytokine Signaling (SOCS) target jaks to downregulate signaling cytokine inducible family of genes which function as feedback inhibitors of signaling  

  18. SOCS proteins inhibit jaks by two mechanisms SOCS recruits ub conjugation complex SOCS binds activated Jak preventing leading to Jak degradation. substrate access. Roc1=RING E3 BC= elonginB,C adaptor Multisubunit E3 ub-ligases

  19. Cancers caused by mi- RNA155

  20. Aberrant expression of microRNA • The majority of human microRNAs are located at cancer-associated genomic regions (Calin et al, 2004a). microRNA expression profiling can distinguish cancers according to diagnosis and developmental stage of the tumour to a greater degree of accuracy than traditional gene expression analysis • MicroRNAs play a direct role in oncogenesis as they can function as both oncogenes (e.g. MIRN155 and members of MIRN17–92 cluster) and tumour suppressor molecules [e.g. MIRN15A (miR-15a) and MIRN16-1 (miR-16-1)]. Aberrant expression of specific microRNAs has now been associated with many types of cancer including solid and haematopoietic tumours

  21. miRNAs and disease Databases http://cmbi.bjmu.edu.cn/hmdd http://www.mir2disease.org/ Cancer (Calin and Croce 2006; Ura et al 2008; Stamatopoulos et al 2009…) Cardiovascular disease (Latronico et al. 2007; van Rooij and Olson 2007) Schizophrenia (Hansen, et al. 2007; Perkins et al. 2007) Renal misfunction (Williams 2007) Tourette syndrome (Esau and Monia 2007) Psoriasis (Sonkoly et al. 2007) Muscle disorders (Eisenberg et al. 2007), X fragile syndrome (Fiore and Schratt 2007) Policitemia vera (Bruchova et al. 2007) Diabetes (Williams 2007) Chronic hepatitis (Murakami et al. 2006) AIDS (Hariharan etal. 2005) Obesity (Weiler et al. 2006, Lovis et al. 2008, Xie et al. 2009).

  22. miRNAs and cancer Tumor formation Oncogene miRNA Tumor suppressor miRNA Upregulation Proliferation Invasion Angiogenesis Cell death • Proliferation • Invasion • Angiogenesis • Cell death Downregulation Esquela-Kerscher & Slack. Nature Reviews Cancer. 2006.

  23. miRNA 155 AND Breast cancer • 1)miR-155 functions as an oncomicroRNA in breast cancer, • 2)decrease the expression of suppressor of cytokine signaling 1 (SOCS1) • 3) in breast cancer cell • 4) overexpression of miR-155 in breast cancer cells • 5) leads to constitutive activation of signal transducer and activator of transcription 3 (STAT3) • 6) by inhibiting SOCS1 expression

  24. References • Kopp KL, et al. miR-155 meets the JAK/STAT pathway. ell Cycle 2013.12:1939-47. PMID:23676217;http://dx.doi.org/10.4161/cc.24987 • Fukuda, M., Gotoh, I., Gotoh, Y., and Nishida, E. (1996). Cytoplasmic localization of mitogen-activated protein kinase kinase directed by its NH2-terminal, leucine-rich short amino acid sequence, which acts as a nuclear export signal. J Biol Chem 271, 20024-20028. • ason S. Rawlings, Kristin M.Rosler and Douglas A. Harrison.2004. The JAK/STAT signalingpathway. Journal of Cell Science 117, 1281-1283. • Taiga Tamiya, Ikko Kashiwagi, Reiko Takahashi, Hideo Yasukawa, Akihiko Yoshimura.2012. Suppressors of Cytokine Signaling (SOCS) Proteins and JAK/STAT Pathways • Regulation of T-Cell Inflammation by SOCS1 and SOCS3. Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association. 31:980-985.

  25. Xu-dong Zhao, Wei Zhang,Hong-jun Liang, Wen-yue Ji.2013. Overexpression of miR -155 Promotes Proliferation and Invasion of Human Laryngeal Squamous Cell Carcinoma via Targeting SOCS1 and STAT3. PLoS ONE 8(2): e56395. • Shuai Jiang, Hong-Wei Zhang, Ming-Hua Lu, et al.2010. MicroRNA-155 Functions as an OncomiR in Breast Cancer by Targeting the Suppressor of Cytokine Signaling 1 Gene. American Association for Cancer. 70:3119-3127. • Akihiko Yoshimura, Mayu Suzuki, Ryota Sakaguchi, Toshikatsu Hanada and Hideo Yasukawa.2012. SOCS, inflammation, and autoimmunity. National Cancer • Research Institute, Italy.vol3:1-9 • Cherie Blenkiron, Leonard D Goldstein, Natalie P Thorne, Inmaculada Spiteri, Suet-Feung Chin, Mark J Dunning, Nuno L Barbosa-Morais, Andrew E Teschendorff , Andrew R Green, Ian O Ellis , Simon Tavaré , Carlos Caldas and Eric A Miska.2007. MicroRNA expression profiling of human breast cancer identifies • new markers of tumor subtype. Genome Biology 2007, 8: R214 .

  26. The End Thank you