Regulation of malignant cell transformation by the stress-activated kinase {p38α [p38-alpha] [Elektronische Ressource] / Ignacio Dolado Pérez

Kundel

Sujets

• Biologie

Informations

• Publié par: ruprecht-karls-universitat_heidelberg
• Publié le: 01 janvier 2007
• Nombre de lectures: 20
• Langue: English
• Poids de l'ouvrage: 8 Mo

Extrait

The Joint Ph.D. Programme of
the European Molecular Biology Laboratory (EMBL) and
the Faculty of Natural Sciences of the Ruprecht-Karls University of Heidelberg







Ignacio Dolado Pérez


Regulation of malignant cell transformation
by the stress-activated kinase p38 α


Ph.D. Thesis











Heidelberg, Germany
June 2007








Dissertation
submitted to the
Joint Ph.D. Programme of the European Molecular Biology Laboratory (EMBL) and the Faculty
of Natural Sciences of the University Ruprecht-Karls of Heidelberg (Germany), for the degree of
Doctor of Natural Sciences


















Diploma chemist: Ignacio Dolado Pérez
Born in: Alicante, Spain













Regulation of malignant cell transformation
by the stress-activated kinase p38 α



















Referees:
Dr. Mathias Treier, Developmental Biology Programme, EMBL, Heidelberg, Germany
Prof. Dr. Claus R. Bartram, Institut für Humangenetik, Heidelberg, Germany This thesis work was carried out at the European Molecular Biology Laboratory (EMBL) in
Heidelberg (Germany) from 2002-2004 and at the Spanish Cancer Center (CNIO) in Madrid
(Spain) from 2004-2006; under the supervision of Dr. Ángel R. Nebreda.





To my mother,

who demonstrated incredible bravery
in fighting cancer and always inspired
my life.

We miss you terribly.











“ Cuando nací, un agosto
ardiente calcinaba las casas.
Al romper en llanto, sintió
mi madre un nudo en la garganta.
Del beso que posó sobre mi cara,
aún noto la tibieza de sus labios.
De sus brazos, que acogieron mi cuerpo,
con ternura, todavía los siento [...]

Y me estremezco ante un beso,
y me quebranto ante un llanto.
Por eso quisiera que mis hijos
amaran como yo,
como mi madre lo hizo ayer
con sus besos y abrazos.
Con esos besos y abrazos
que aún llevo impresos en
los pliegues de mi piel.”


Maria del Carmen Llavador. Palabras CONTENTS
TABLE OF CONTENTS


TABLE OF CONTENTS ............................................................................................................. I
ACKNOWLEDGEMENTS ...................................................................................................... III
SUMMARY ................................................................................................................................ IV
ZUSAMMENFASSUNG (SUMMARY IN GERMAN) .......................................................... V
RESUMEN (SUMMARY IN SPANISH) ................................................................................ VI
PUBLICATIONS ..................................................................................................................... VII
CONTRIBUTIONS TO PUBLICATIONS ......................................................................... VIII
ABBREVIATIONS ................................................................................................................... IX
INTRODUCTION ....................................................................................................................... 1
1. MALIGNANT TRANSFORMATION, TUMORIGENESIS AND CANCER ...................... 2
A) Concept definition .............................................................................................................. 2
B) Traits of the cancer cell and how to analyze them technically .......................................... 2
B.1) Immortalization .......................................................................................................... 3
B.2) Independence of extracellular growth signals ............................................................ 4
B.3) Independence of anti-growth signals ......................................................................... 6
B.4) Apoptosis evasion ...................................................................................................... 7
B.5) Sustained angiogenesis .............................................................................................. 8
B.6) Invasion and metastasis ............................................................................................. 9
C) Cancer at the molecular level ........................................................................................... 11
C.1) Cancer is an evolving and dynamic genetic disease ................................................ 11
C.2) Target cells in carcinogenesis .................................................................................. 13
C.3) Cancer as a systemic disease: beyond oncogenes and tumor suppressors .............. 15
C.4) The double-edged role of free radicals in cancer ..................................................... 16
C.4.1) The chemical nature of free radicals ............................................................... 16
C.4.2) Cancer as a disease of free radicals overload .................................................. 18
C.4.3) Free radicals in the clinics: a word of caution ................................................ 20
C.5) Detoxification enzymes in cancer: cleaner is not always better .............................. 21
C.5.1) Antioxidant versus detoxification enzymes .................................................... 21
C.5.2) Detoxification enzymes and cancer: a matter of equilibrium ......................... 23
D) Human cancer in the clinics: current status and future perspectives ............................... 25
2. MITOGEN-ACTIVATED PROTEIN KINASES ................................................................. 28
E) The mitogen-activated protein kinase (MAPK) family. A brief overview ...................... 28
F) Signal transduction by p38 MAPK .................................................................................. 31
F.1) Upstream activators .................................................................................................. 31
F.2) Downstream targets .................................................................................................. 32
iCONTENTS
F.3) Regulation of gene expression by p38 MAPK ......................................................... 33
F.3.1 Transcriptional regulation ........................................................................... 33
F.3.2 Translational regulation .............................................................................. 37
G) p38 MAPK roles in cancer .............................................................................................. 37
G.1 Tumor-suppressive roles: proliferation, differentiation and survival ....................... 38
G.2 Oncogenic activities: inflammation, invasion, angiogenesis and migration ............. 41
H) p38 MAPK as a putative target in cancer therapy? ......................................................... 43
OUTLOOK ................................................................................................................................. 44
BIBLIOGRAPHY ...................................................................................................................... 45
APPENDIX.. 59
• DOLADO I., NEBREDA A.R.
Regulation of tumorigenesis by p38 α MAP kinase.
In: Nebreda A.R. and Posas F. (Ed.): SAPKs - Stress-Activated Protein Kinases.
Springer-Verlag, Top Curr Genet. 19 (in press).................................................................... A1

• DOLADO I., SWAT A., AJENJO N., DE VITA G., CUADRADO A., NEBREDA A.R.
p38α MAP kinase as a sensor of reactive oxygen species in tumorigenesis.
Cancer Cell 2007 Feb;11(2):191-205.................................................................................... A2

• ALFONSO P., DOLADO I., SWAT A., NUNEZ A., CUADRADO A., NEBREDA A.R.,
CASAL J.I.
Proteomic analysis of p38 α mitogen-activated protein kinase-regulated changes in membrane
fractions of RAS-transformed fibroblasts.
Proteomics 2006 Apr;6 Suppl 1:S262-271............................................................................ A3

• FAUST D., DOLADO I., CUADRADO A., OESCH F., WEISS C., NEBREDA A.R.,
DIETRICH C.
p38α MAPK is required for contact inhibition.
Oncogene 2005 Nov 24;24(53):7941-7945........................................................................... A4

• ROUSSEAU S., DOLADO I., BEARDMORE V., SHAPIRO N., MARQUEZ R.,
NEBREDA A.R., ARTHUR S.C., TESSIER-LAVIGNE M., GAESTEL M., CUENDA A.,
COHEN P.
CXCL12 and C5a trigger cell migration via a PAK1/2-p38 α MAPK-MAPKAP-K2-HSP27
pathway.
Cell Signal. 2006 Nov;18(11):1897-1905.............................................................................. A5

• CUADRADO A., LAFARGA V., CHEUNG P., DOLADO I., LLANOS S., COHEN P.,
NEBREDA A.R.
A new p38 MAP kinase