TY  - GEN
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/7422/
ID  - heidok7422
TI  - Regulation of malignant cell transformation by the stress-activated kinase p38alpha
Y1  - 2007///
AV  - public
A1  - Dolado Pérez, Ignacio
N2  - Cancer is a dynamic process that requires the stepwise deregulation of mechanisms affecting various cellular traits. During my PhD, I have characterized how the stress-activated p38alpha MAPK signaling pathway regulates the processes of cellular migration, proliferation, and survival in the context of oncogene-induced malignant transformation, which recapitulates the mechanisms of cancer initiation at the cellular level. My studies have been mostly based on the use of human and mouse cultured cells, which I have analyzed using both biochemical and cell biological approaches. In particular, the development of p38alpha-deficient cell lines and the application of retrovirally-based gene expression techniques have been very useful. The implementation of tools to measure the intracellular levels of reactive oxygen species (ROS) within living cells has also been key for my work. I have found that p38alpha regulates the process of malignant transformation at various levels. First, p38alpha negatively regulates cell cycle progression induced by mitogenic signals in both exponentially proliferating and confluent cells. Oncogene-expressing cells proliferate faster in the absence of p38alpha, which may be accounted for by the negative effect of p38alpha on cyclin D1 expression. Similarly, p38alpha controls the process of cell-cell contact-inhibition, which requires p27Kip1 accumulation and triggers G1-phase cell cycle arrest upon cell confluence. The process of contact inhibition is likely to involve uncharacterized membrane-associated signaling events. Accordingly, I have found that p38alpha regulates the membrane composition of oncogene-transformed cells. In addition to its negative role in cell proliferation, I have shown that p38alpha can interfere with the process of malignant transformation by sensing oxidative stress and inducing apoptosis. Thus, p38alpha becomes activated when oncogene-expressing cells accumulate high levels of carcinogenic ROS and, in turn, induces the elimination of the transformed cells by apoptosis. Interestingly, I have found that human cancer cell lines that contain high ROS levels have developed a mechanism to by-pass this p38alpha function. Finally, in contrast to its anti-proliferative and pro-apoptotic roles, I have found that p38alpha is an important mediator of cytokine-induce cell migration, a process that is thought to be important for cancer cell metastasis.
KW  - Zelltransformation 
KW  -  krebs 
KW  -  stress 
KW  -  p38 MAPK 
KW  -  Zellmigration 
KW  -  Ras 
KW  -  p27Kip1 
KW  -  Zellwachstum 
KW  -  reaktiven SauerstoffradikalenGST 
KW  -  p38 MAPK 
KW  -  cell transformation 
KW  -  ROS 
KW  -  oxidative stress 
KW  -  apoptosis 
KW  -  migration 
KW  -  contact inhibition
KW  -  proliferation 
KW  -  Ras 
KW  -  oncogenes
ER  -