The role of Notch signaling in development and tumorigenesis [Elektronische Ressource] / Pawel Karol Mazur

Pawel Mazur

Sujets

• Biologie

Informations

• Publié par: technische_universitat_munchen
• Publié le: 01 janvier 2010
• Nombre de lectures: 65
• Langue: English
• Poids de l'ouvrage: 5 Mo

Extrait

TECHNISCHE  UNIVERSITÄT  MÜNCHEN  
 
Lehrstuhl  für  Humanbiologie  
 
 
 
Title  page  
 
 
 
The  role  of  Notch  signaling  in  development  and  tumorigenesis  
 
 
 
 
Pawel  Karol  M azur  
 
 
 
 
 
 
Voler   Abdruck  der  von  der  Fakultät  Wissenschaftszentrum  Weihenstephan  für  
Ernährung,   Landnutzung   und   Umwelt   der   Technischen   Universität   München   zur  
Erlangung  des  akademischen  Grades  eines  
 
 
Dokors  der  Na    
 
 
genehmigten  Dissertation.  
 
 
Vorsit :   Univ.-­‐Prof.  Dr.  M.  Klirngepons  
 
Prüfer  der  Dissert   1.    Univ.-­‐Prof.  Dr.  M.  Schemann  
 
2.    Univ.-­‐Prof.  Dr.  R.  M.  Schmid  (schriftiche  Bung)  
 
3.    Univ.-­‐Prof.  Dr.  M.  Hra é  de  Angelis  
 
 
Die   Dissertation   wurde   am   10.02.2010    ibe  red n  ehcsnihceT tät  isrevniU n  Münceh
  und   durch   die   Fa   W m   Weihenstephan    
r   ,   Lungandnutz   und   Umwelt   am   21.10.2010   angenommen.

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dignstälSummary  
 
In  this  thesis,  the  role  of  the  Notch  signaling  pathway  in  pancrnd  liver  eas  a development  
as  well  as  in  pancreas  and  skin  tumorigenesis  was  investigated   using  chemically  and  
genetically   engineered   mouse   models.   The   obtained   results   underscore    thigh  he
importance  of  Notch  signaling  in  tissue  maturation,  homeostasis  and  disea  se.  
Pancreas   development   is   thought   to   depend   strongly   on   proper   Notch   pathway  
regulation.  However,  the  current  study  provides  proof  that  Notch1  and  Notch2  receptor  
ablation   only   moderately   disturbs   this   process.   In   contrast,   ablation   of   the   Notch  
signaling   effector   Rbpj   dramatically   impairs   exocrine   cell   expansion   and   leads   to  
premature   differentiation   of   progenitor   into   endocrine   cells.   This   study   identifies  
elements   of   Notch   pathway   crucial   for   pancreas   development   and   may   have   a  
significant  influence   or  regenerative  medicine.  f  
In  addition,  the  Notch  pathway  was  found  to  be  critical  for  pancreas  recovery  after  
acute  pancreatitis.  The  presented  results  indicate  that  Notch  signaling  is  essential  for  
pancreatic  exocrine  cell  regeneration  after  acute  mation   inflamthrough  modulation  of  
the  β-­‐catenin  pathway.  These  results  provide  a  better  understanding  of  the  molecular  
pathways   involved   in   the   acute   pancreatitis –  a     disease   that   displays  serious  
complications  and  high  mortality.  
Also,  during  liver  maturation   Notch  signaling  was  found  to  be  crucial.  In  here,  evidence  
is   provided   for   an   essential   role   of   the   Notch2   receptor   in   intrahepatic   bile   duct  
formation.  This  finding  is  especially  important  since  the  presented  liver  specific  Notch2  
ablated   mice   recapitulated   features   of   the   human   Alagille   Syndrome   (AGS).   This  
multisystem  disorderis    characterized  by  developmental  abnormalities    heaof  thert,  eye,  
skeleton,  and  liver.  The  results  reveal  molecular  mechanisms  that  may  contribute  to  
AGS  formation.  
Finally,  the  thesis  marks  the  prominence  of  the  Notch  pathway  in  tumorigenesis  and  
cancerous  cell  fate  decisions.   This  study  elucidates  the  role  of    in  Nottwoch  highly  
malignant  (pancreatic  cancer)  and  frequent  (skin  cancer)neoplasias   .  Skin  tumors,  with  
an  incidence  rtea  in  Europe  of  over  1  million  per  year,  are  the  most  common  human  
neoplasias  and  pancreatic  ductal  adenocarcinoma  (PDAC),  although  less  prevalent,  has  
the   highest,   exceeding   95%,   mortality   rate   among   all   The  cancers.  utilized   mouse  
models  reveal  the  cell-­‐context  dependent  and  doub -­‐edged  Notle ch  signal  ingeffect.  s  
In  the  study  of  skin  tumor  mouse  models,th   e  role  of  Notch  but  1 not  Notch2  as  a  tumor  
suppressor  was  confirmed.   Tumor  suppressing  mechanisms  of   Notch1  in  the  epidermis  
involved  modulation   of   β-­‐catenin   and   p21   signaling.   Also   Notch1   but   not   Notch2  
deletion  alters  hair  follicles  development  suggesting  an  essential  role  of  Notch1  in  skin  
homeostasis.  Additionally,  this  study  revealed  a  previously  unrecognized  expression  of  
the  pancreatic  transctiriopn  factor  Pdx1  in  the  ski   n.
In  contrast  to  cutaneous  neoplasias,  investigation s  of  the  PDAC  mouse  model   identifies  
Notch2  as  pro-­‐oncogen icin     the  early  development  thof  e  disease.  Its  pancreas  specific  
G12Ddeletion  in  the  established  oncogenic  Kra-­‐s induc ed  tumor  mouse  model  leads  to  
prolonged  survival  with  a  lockb  in  preneoplastic  lesion  progression  and  late  appearing  
anaplastic  PDAC.  Pancreatic  Notch2  activates  Myc  signaling  and  Notch2  deletion  leads  
to   epitheli-­‐alto-­‐mesenchymal   transition,   while  Notch1   has   no   major   role   in   PDAC  
initiation  and  progression.  
Understanding   the  molecular  biology  of  cancer  is  essentialto  dev  elop  new  therapie  s.
Thepr  esented  results  provide  insights  of  Notch  signaling  functions  and  may  open  new  
routes  for  cancer  treatment.  
2    Zusammenfassung  
 
In  dieser  Doktorarbeit  wurde  der  Beitr  des   ag Notch  Signalweges   für  die  Entwicklung  
von   Pankreas   und   Leber  sowie   für   die   Tumorentstehung   in   Pankreas   und   Haut  
untersucht.   Hierfür   wurden   genetisch   und   chemisch   veränderte   Mausmodelle  
verwendet.   Die