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Wnt signaling

Wnt signaling. http://www.stanford.edu/~rnusse/wntwindow.html Wnt website. Wnt proteins a family of highly conserved secreted signaling molecules that regulate cell-to-cell interactions during embryogenesis Wnt genes and Wnt signaling are also implicated in cancer.

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Wnt signaling

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  1. Wnt signaling http://www.stanford.edu/~rnusse/wntwindow.html Wnt website

  2. Wnt proteins • a family of highly conserved secreted signaling molecules that regulate • cell-to-cell interactions during embryogenesis • Wnt genes and Wnt signaling are also implicated in cancer. • Insights into the mechanisms of Wnt action have emerged from several • systems: genetics in Drosophila and C. elegans; biochemistry in cell • culture and ectopic gene expression in Xenopus embryos. • Many Wnt genes in the mouse have been mutated, leading to very • specific developmental defects. • As currently understood, Wnt proteins bind to receptors of the Frizzled • family on the cell surface. Through several cytoplasmic relay • components, the signal is transduced to beta-catenin, which then • enters the nucleus and forms a complex with TCF to activate • transcription of Wnt target genes.

  3. A model for Wnt/wg signaling

  4. Wnts are secreted from cells • albeit rarely in a soluble form.

  5. In the extracellular space • Several secreted proteins can bind directly to Wnts, to modulate Wnt activity.

  6. In cells not exposed to the Wnt signal • β-catenin levels are kept low through interactions with the protein kinase zw3/GSK-3β, APC and Axin

  7. GSK-3β • GSK-3β는 APC와 결합하여 beta-catenin과 complex를 형성하여 beta-catenin의 양을 조절하여 세포증식 및 분화를 down regulation하는 것으로 알려져 있습니다.

  8. β-catenin is degraded • After phosphorylation by GSK-3β, through the ubiquitin pathway, involving interactions with Slimb/b-TrCP. • The DIX domain in Axin is similar to the NH2 terminus in Dsh, and promotes interactions between Dsh and Axin. • Axin also binds to the phosphatase PP2A, while the B56 subunit of PP2A interacts with APC.

  9. APC • APC는 결장암에서 90% 이상이 돌연변이를 보이는 것으로도 알려져 있다. APC의 주요 기능은 베타-카테닌의 함량을 저하시키는 것으로 알려져 있는데, 일단 APC 유전자에 돌연변이가 일어나면 베타-카테닌의 함량이 증가해 이 물질이 핵 내부로 침투하는 결과를 빚게 된다.

  10. Loss of APC in mammalian cells can also lead to a critical loss over Arm control, leading to cell transformation. APC has a specific function in keeping β-catenin out of the nucleus. There are many other proteins binding to APC.

  11. beta-catenin • β-Catenin plays a dual role in the cell: one in linking the cytoplasmic side of cadherin-mediated cell-cell contacts to the actin cytoskeleton and an additional role in signaling that involves trans activation in complex with transcription factors of the lymphoid enhancing factor (LEF-1)family.

  12. Elevated β-catenin levels in colorectal cancer caused by mutations in β-catenin or by the APC, which regulates β-catenin degradation, result in the binding of β-catenin to LEF-1 and increased transcriptional activation/repression.

  13. The Wg/Wnt signal leads • In a current model, Wnt signaling initially leads to a complex between Dsh, GBP/Frat1, Axin and Zw3/GSK, which may be the regulatory step in the inactivation of Zw3/GSK. • As a consequence, GSK does not phos- phorylate β-catenin anymore, releasing it from the Axin complex and accumulation. Binding of Axin to the cytoplasmic tail of LRP in a Wnt dependent manner may also play a role in rearranging this complex.

  14. In the nucleus • In the absence of the Wnt signal,TCF acts as a repressor of Wnt/Wg target genes. • TCF can form a complex with Groucho. The repressing effect of Groucho is mediated by interactions with HistoneDeacetylases (HDAC). β-catenin can convert TCF into a transcriptional activator of the same genes that are repressed by TCF alone.

  15. Domains and binding sites on TCF Groucho Amadillo/b-catenin HMG box TCF K25 CBP

  16. Among the target genes • Of this pathway are the c-myc gene, is activited in colon cancer by loss of APC. • Another target of β-catenin is Cyclin D.

  17. TCF (T cell factor) High mobility group B-catenin binding site βBD HMG B box • LEF-1 (Lymphoid enhancer factor) CTA Context-dependent transactivation domains βBD A B HMG HA • β-catenin α- catenin APC Protein stability cadherin 1 781 N-TA C-TA LEF-1 / TCF

  18. Gene Mutant Phenotype Gene Species/GenBank mutant phenotype TCF1 Mouse Tcf-1 also called Tcf-7 Thymocyte Differentiation additional neural tubes defects in the formation of the placenta and in the development of limb buds in double mutant with Lef-1 Mammary tumors, accelerated by loss of Min/APC

  19. Gene Species/GenBank mutant phenotype TCF3 Mouse Tcf-3 also called Tcf-7 Headless gene (hdl) in Zebrafish, essential in head formation

  20. Gene Species/GenBank mutant phenotype TCF4 Mouse Tcf-4 also called Tcf7 Absence of epithelial stem cells in small intestine

  21. Gene Species/GenBank mutant phenotype LEF1 Mouse Lef-1 Several organs, epithelial-mesenchymal interactions additional neural tube defects in the formation of the placenta andin the development of limb buds in double mutant with TCF-1 Defects in pro-B Cell proliferation and survival

  22. This is a list of target genes of Wnt/β-catenin signaling gene Organism Direct/indirect Up/down Ref. C-myc Human colon cancer yes up He 1998 Cyclin D Human colon cancer yes up Tetsu 1999 Tcf-1 Human colon cancer yes up Roose 1999 PPARdelta Human colon cancer yes up He TC 1999 c-jun Human colon cancer yes up Mann B, 1999 fra-1 Human colon cancer yes up Mann B, 1999 uPAR Human colon cancer yes up Mann B, 1999 MMP-7 Human colon cancer yes up Crawford 1999 CD44 Human colon cancer yes up Wielenga 1999

  23. Cyclin D1 • 사이클린 D1은 세포 생장을 조절하는 주요 조절 인자 가운데 하나이기 때문에 사이클린 D1 단백질에 이상이 생기게 되면 세포 분열(cell proliferation)이 급격히 증가하게 되는 결과를 빚는다. 이로 인해 세포 조직이 비정상적으로 생장하게 되고 결국에는 종양(tumour)이 형성되는 것이다.

  24. C-myc • 사람의 c-myc 유전자는 nuclear oncogene으로 8번 염색체에 위치하며, 3개의 exon으로 구성되어 있다. 여기서 exon 1은 조절역할을 하며 exon 2, 3이 합쳐져 단백질을 만들게 된다. c-myc은 대장암, 자궁경부암, 폐암, 소세포폐암, 유방암, 위암, 생식기암, 결장암, 위선암, 전골수세포 백혈병, 섬유 아세포증, 상피세포증, 골수세포증 등 발암유전자중에서도 가장 많은 종류의 암에 관련이 있다.

  25. 또한 염색체 전좌에 의해 c-myc 유전자의 활성화가 Burkitt's 임파종 (BL)에서도 발견되고 있다 (translocation 때 mutation). 이것은 암세포 형성의 직접적인 원인 보다는 ras 등 다른 발암유전자등과 함께 작용하여 세포를 변형시키는 조력자의 역할을 하는 것으로 알려져 있는데, 보통 증폭이 빠르고 악성 빈도가 높은 암에서 나타난다. 그러므로 c-myc 발암유전자의 활성으로서 또 다른 발암유전자의 발현을 예측할수 도 있다. 암 유발 유전자인 c-myc 또한 세포사를 촉진시키는 것으로 알려졌다

  26. 암에서의 양상추론 • β-catenin이 암에서는 E-cadherin과 떨어진다. • β-catenin은 GSK-3β에 의해서 인산화 되지않는다. • APC 돌연변이 • β-catenin, LEF/TCFs 발현증가 • β-catenin 자체의 mutation • Wnt pathway activation

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