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THE ROLE OF NOTCH IN TUMORIGENESIS: ONCOGENE OR TUMOUR SUPPRESSOR?

THE ROLE OF NOTCH IN TUMORIGENESIS: ONCOGENE OR TUMOUR SUPPRESSOR?. Speakers: 葉恭誌 李昭鋐 組員 : 林雅葶 張明俐 羅苑菁 鄭伯忻 曾昭穎 蔡志文 陳美君 江承堯 高家民 呂女秀菱. Notch. notch. notch.

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THE ROLE OF NOTCH IN TUMORIGENESIS: ONCOGENE OR TUMOUR SUPPRESSOR?

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  1. THE ROLE OF NOTCH IN TUMORIGENESIS: ONCOGENE OR TUMOUR SUPPRESSOR? Speakers: 葉恭誌 李昭鋐 組員: 林雅葶 張明俐 羅苑菁 鄭伯忻 曾昭穎 蔡志文 陳美君 江承堯 高家民 呂女秀菱 Notch

  2. notch notch - In 1917,Thomas Hunt Morgan and colleagues described a strain of Drosophila with notches at the end of their wing blades. • Notch: • Genetics: Haploinsufficiency • Structure: transmembrane receptor

  3. Transcription activation domain CDC10 repeats Lin12 repeats (cysteine-rich) Nuclear-localization signal Structure : transmembrane receptor • Synthesized as a single precursor protein • Cleaved in two during its transport to the cell surface. Notch receptor Drosophila Ligand (Delta) (Serrate)

  4. Human Notch receptor Ligand EGF ANK RAM LN PEST TAD (Ser-like) Slight difference

  5. Notch signaling • Different modification of Notch and signal crosstalk influence Notch activation. • Different cell type uses different signal. Activation leads to cleavage IC domain (Notch IC) Translocate into nucleus and bind to transcription factor CSL Notch absence: transcription repressor Notch present: Transcription activator • HES (hairy/enhancer of split) family of transcription factors • cell-cycle regulator-Waf1

  6. Notch function

  7. Notch function • Maintenance of an undifferentiated state • Notch signaling can maintain stem cells or precursor populations in an undifferentiated state. • Gain-of-function studies:(in the chicken) • using a dominant active Notch-IC:Notch signaling prevents progenitors from undergoing neurogenesis. • blocking the Notch pathway:excessive neurogenesis and depletion of the progenitor pool. Lewis, J. (1998) Semin. Cell Dev. Biol. 9, 583–589 Henrique, D. (1997) Curr. Biol. 7, 661–670

  8. receptor ligand Equitpotent cell ? Differentiation Equitpotent cell • During the development of neuronal-precursor cells of the sensory organ in Drosophila. Participate in Cell-fate decision Epidermal cell Neuronal cell

  9. Inductive cell-fate determination Notch signal Example : bipotential mouse neural-crest stem cell adopt to glial cell. Cell differentiation Mouse thymic epithelial cell T-cell Early lymphocyte precursors B-cell

  10. Induction of terminal differentiation • DLL1-induced Notch signaling initiates a terminal-differentiation program in human skin. • Other possible mechanism (Jagged-mediated):activated Notch1 causes keratinocyte growth arrest through increased p21WAF1/Cip1 expression. —Rangarajan, A. (2001) EMBO J. 20, 3427–3436

  11. Notch as an oncogene

  12. Notch and T-cell leukaemia • Translocation of a portion of chromosome 7 to chromosome 9, which contains T-cell receptor-b gene. • Expreesion of truncated NOTCH1 transcripts (similar to NOTCH1-IC) from TCRb promoter causes T-cell acute lymphoblastic leukaemia (T-ALL). Ellisen, L. W. et al. Cell66, 649-661 (1991).

  13. Hot spots of mutations found in more than 50% of T-ALL patients HD: heterodimerization domain P: pest domain. Weng AP. et al.Science 306:269–271(2004)

  14. Why does the hematopoietic oncogenic potential seem to be restricted to T cell leukemia? • Mice transplanted with Notch1-IC-expressing bone-marrow-progenitor cells from either Rag2–/– or Slp76 –/– mice failed to develop T-cell • leukaemia. • Introduction of a TCR βtransgene into Rag2–/– mice — to re-activate pre- • TCR signalling — restored the oncogenic function of Notch1-IC. Allman, D. et al. J. Exp. Med. 194, 99–106 (2001). Notch1-IC-mediated transformation is dependent on a second T-cell-specific signal that is mediated by the pre-TCR.

  15. Notch and viruses • Proviral integration of the Moloney murine-leukaemia virus (MuLV) into the murine Notch1 locus causes T-ALL in mice. • Integration of the mouse mammary tumour virus (MMTV) in between the Notch/Lin12 repeats and the transmembrane domain of either the Notch1 (NI) or Notch4 (N4) gene causes mammary tumours in the mouse.

  16. Notch and Epithelial tumours • Transgenic mice that express this Notch4-IC/int-3gene developed poorly differentiated mammary and salivary-gland adenocarcinomas within 7 months. • The mammary epithelial of these mice failed to branch.

  17. Notch-IC (1) RAM domain : CBF binding site (2) ankyrin repeat domain (ANK) : mediates further protein- protein interactions (3) C-terminal domain : a polyglutamine region (OPA) + proline, glutamic acid, serine and threonine rich region (PEST) (4) NLS : nuclear localization sequence

  18. How can Notch contribute to transformation? • CBF1 is a sequence specific DNA binding protein that functions to repress transcription of cellular genes • In some cells, Notch-assisted transformation is dependent on the ankyrin repeats of the Notch protein, not CBF1

  19. E1A-immortalized baby rat kidney cell line (RKE) MOLECULAR AND CELLULAR BIOLOGY, June 2000, p. 3928–3941

  20. Notch needs to partner another oncoprotein to actually cause cancer Virology 286, 23±30 (2001) AcN1: a truncated allele of Notch1 Transformation can be induced by expressiong Notch-IC with oncoproteins such as adenovirus EIA,HPV E6 and E7…

  21. These oncoproteins all share the common property of being able to override the G1-S checkpoint resistance to apoptosis, anoikis or differentiation ANOIKIS: Cell death induced as a result of the absence of matrix attachment

  22. The oncogenic effects of Notch include PI3-K activation and induction of ERBB2 and NF-ĸB2 expression (by NOTCH-IC) • PI3-K resistance to anoikis • ERBB2 cell proliferation and growth • NF-ĸB2 expression of genes which encode anti-apoptotic proteins

  23. Notch1 as tumour suppressor NOTCH1 signaling increases expression of WAF1, which causes cell-cycle arrest in basal cells, to allow the onset of terminal differentiation

  24. In Notch1-ablated skin, reactivation of Wnt and Sonic-hedgehog pathways result in the development of basal-cell-carcinoma-like tumours in the mouse. • The tumour-suppressive activity of NOTCH1 might be mediated by several routes, to induce cell-cycle arrest and differentiation • Tumour cells might counter-select against expression of Notch receptors or ligands to escape from differentiation and cell-cycle arrest

  25. The two faces of Notch in cervical cancer

  26. Proteins are increasingly being found to have several and possibly opposing functions

  27. HPV was found in 99% cervical cancers

  28. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53 1990 Cell • Telomerase activation by the E6 gene product of human papillomavirus type 16 1996 Nature =>E6 and E7 are oncoproteins in cervical cancer cells

  29. BUT….. =>Notch prevent cellular proliferation in normal epithelia =>upregulate WAF1 =>cells initiation of differentiation

  30. Conclusion • The outcome of Notch activation is dependent on cellular context

  31. Thank you

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