Docstoc

WNT signaling

Document Sample
WNT signaling Powered By Docstoc
					The Wnt signal transduction pathway
  a crucial regulatory mechanism underlying
          differentiation and disease

                David J.J. de Gorter
               D.de_Gorter@lumc.nl




          Leiden University Medical Center
                  The Netherlands
WNT signaling plays an essential role
 in differentiation and development



   WNT signaling regulates polarity,
    gastrulation and organogenesis



   WNT signaling controls proliferation,
    differentiation, migration and cell-cell
    communication
      WNT signaling plays
an essential role in development
Canonical WNT signaling

                          Target genes

                              MYC
                            CCND1
                              JUN
                               TCF
                               LEF
                             PPARD
                              upar
                             MMP7
                             AXIN2
                            NrCAM
                               TF2
                             Gatrin
                              CD44
                              MET
                            ephrinB
                             BMP4
                            Claudin
                             VEGF
                               ID2
                              Twist
                          stromelysin
Drosophila         Vertebrates                    C. elegans   Dictyostelium
  Wingless          Wnt-1            Ligands        Wnt           cAMP


  Frizzleds,        Frizzled,                                      Zak
  Arrows            LRP5/6
                                    Receptors


  Dishevelled        Dishevelled


  Axin,             Axin, GSK3,    Destruction      GSK-3         Gsk-A
  Zeste-white 3,    APC             Complex
  APC

                                     Nuclear
  Armadillo         b-catenin       Signaling       Wrm-1          Aar


                                   Target Genes
                 WNT signaling controls cell fate
                        in the intestine
                         Villus
                         ~3.500 cells        Apoptotic cells                      b-catenin expression

  Stem cells
  Paneth cells
  Transient-amplifying
  cells

  Absorptive cells
  Goblet cells                 Absorptive   Goblet      Entero-       Paneth
                               cell         cell     endocrine cell   cell
  Enteroendocrine
  cells




Mouse of
 crypt
                                             Transient amplifying cell



                                  Specialized
                                  intestinal cells in
                                  crypt and villus
                                                                         WNTs are Morphogens:
    Crypt
  ~250 cells
                           Transient                                     Diffusible signaling molecules
                           amplifying cells                              capable of imposing a pattern
                             Stem cells in
                                                                         on a whole field of cells
                             the lower crypt
 Deregulated WNT signaling pathway


Mutations in APC or b-catenin (CTNNB1) genes

             Stabilization of b-catenin
             Altered expression of TCF target genes

Cancer:      Colorectal cancer (CRC)
             Gastric carcinoma
             Hepatocellular carcinoma
             Fibromatosis
             Melanoma
             Medulloblastoma
             Prostate cancer
Familial Adenomatous Polyposis (FAP) is a multi-organ tumor
  predisposition and is caused by germline APC mutations

                                                             Mesenteric
                                                             desmoid




                                           Epidermal cysts

                          Colonic polyps




                       Duodenal polyp
WNT/b-catenin signaling

                          Target genes

                              MYC
                            CCND1
                              JUN
                               TCF
                               LEF
                             PPARD
                              upar
                             MMP7
                             AXIN2
                            NrCAM
                               TF2
                             Gatrin
                              CD44
                              MET
                            ephrinB
                             BMP4
                            Claudin
                             VEGF
                               ID2
                              Twist
                          stromelysin
WNT/b-catenin signaling        ~85% of the CRC cases:
                             inactivating APC mutations
in CRC      Normal        APC mutations
                                           Target genes

                                                MYC
                                              CCND1
                                                JUN
                                                 TCF
                                                 LEF
                                               PPARD
                                                upar
                                               MMP7
                                               AXIN2
                                              NrCAM
                                                 TF2
                                               Gatrin
                                                CD44
                                                MET
                                              ephrinB
                                               BMP4
                                              Claudin
                                               VEGF
                                                 ID2
                                                Twist
                                            stromelysin
 intestinal
                        ACF                adenoma               carcinoma
epithelial cell


                                                       SMAD2/4         p53
                  APC              K-RAS             chr. 18q LOH chr. 17p LOH


                              signal transduction & chromosomal instability
Multiple intestinal neoplasia (Min) mouse;
 a genetic model of intestinal neoplasia




•   Mice heterozygous for an APC
    mutation at codon 850 (APC+/Min
    mice) are used as a model for
    FAP

•   Similar to FAP patients these
    mice develop multiple
    adenomas in the intestine
WNT/b-catenin signaling      ~15% of the CRC cases:
                           oncogenic b-catenin mutation
in CRC      Normal        b-catenin mutations
                                            Target genes

                                                MYC
                                              CCND1
                                                JUN
                                                 TCF
                                                 LEF
                                               PPARD
                                                upar
                                               MMP7
                                               AXIN2
                                              NrCAM
                                                 TF2
                                               Gatrin
                                                CD44
                                                MET
                                              ephrinB
                                               BMP4
                                              Claudin
                                               VEGF
                                                 ID2
                                                Twist
                                            stromelysin
WNT/b-catenin signaling        ~85% of the CRC cases:
                             inactivating APC mutations
in CRC      Normal        APC mutations




                           MYC
                          CCND1
     Cyclin D1 (CCND1) in CRC


 Controls cell cycle progression


 Over-expressed in many colon carcinomas,
  although the gene is rarely amplified

 b-catenin activates transcription from the
  cyclin D1 promoter

 Dominant negative TCF causes G1 arrest in
  CRC cells; this can be rescued by over-
  expression of Cyclin D1
                MYC in CRC


 The proto-oncogene c-MYC is a target of the
  Wnt pathway


 Deletion of MYC rescued the perturbed
  differentiation, migration, proliferation and
  apoptosis caused by loss of APC
Loss of MYC causes APC-deficient crypts
      to resemble wild-type crypts




                    Sansom et al., Nature (446) 676-679, 2007
                MYC in CRC


 The proto-oncogene c-MYC is a target of the
  Wnt pathway


 Deletion of MYC rescued the perturbed
  differentiation, migration, proliferation and
  apoptosis caused by loss of APC


 MYC is required for activation of the majority
  of Wnt target genes following APC loss
               Conclusion



 WNT signaling plays an essential role
  in differentiation and development


 Deregulated WNT signaling due to APC or
  b-catenin mutations results in tumorigenesis


 The WNT target genes Cyclin D1 and MYC
  play an important role in CRC tumorigenesis

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:7
posted:3/29/2012
language:
pages:19