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Summary. Non Coding RNA MiRNA History mi RNA F unctions 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- RNA 155. MiRNA History.

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summary
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
slide4
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).
slide5
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)
slide6
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)
mi rna pathway
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

mi rna locatation
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).
mi rna role in regulation of teranscription
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
data based modeling of the jak stat pathway
Data-based Modeling of the JAK-STAT Pathway
  • a receptor
  • Janus Kinase (JAK)
  • Signal Transducer and Activator of Transcription(STAT)
slide16
Structural and Functional Domains of JAK Family

JAK family : JAK1, JAK2, JAK3 and TYK2

Nat. Rev. Mol. Cell Biol. 2002 3:651

stats s ignal t ransducers and a ctivators of t ranscription
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.
the jak stat signalling pathway
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
canonical jak stat pathway
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.
slide21
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

negative regulation of the jak stat pathwey
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)
s uppressor o f c ytokine s ignaling socs target jaks to downregulate signaling
Suppressor Of Cytokine Signaling (SOCS) target jaks to downregulate signaling

cytokine inducible family of genes which function as

feedback inhibitors of signaling  

slide24
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

slide27
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

slide29
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).

slide30
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.

mirna 155 and breast cancer
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
references
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.
slide33
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 .
slide34
The End

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