BAG-1 haplo-insufficiency impairs lung tumorigenesis.
BACKGROUND
BAG-1 is a multifunctional co-chaperone of heat shock proteins (Hsc70/Hsp70) that is expressed in most cells. It interacts with Bcl-2 and Raf indicating that it might connect protein folding with other signaling pathways. Evidence that BAG-1 expression is frequently altered in human cancers, in particular in breast cancer, relative to normal cells has been put forward but the notion that overexpression of BAG-1 contributes to poor prognosis in tumorigenesis remains controversial.


METHODS
We have evaluated the effect of BAG-1 heterozygosity in mice in a model of non-small-cell lung tumorigenesis with histological and molecular methods. We have generated mice heterozygous for BAG-1, carrying a BAG-1 null allele, that in addition express oncogenic, constitutively active C-Raf kinase (SP-C C-Raf BxB) in type II pneumocytes. SP-C C-Raf BxB mice develop multifocal adenomas early in adulthood.


RESULTS
We show that BAG-1 heterozygosity in mice impairs C-Raf oncogene-induced lung adenoma growth. Lung tumor initiation was reduced by half in BAG-1 heterozygous SP-C C-Raf BxB mice compared to their littermates. Tumor area was reduced by 75% in 4 month lungs of BAG-1 haploinsufficient mice compared to mice with two BAG-1 copies. Whereas BAG-1 heterozygosity did not affect the rate of cell proliferation or signaling through the mitogenic cascade in adenoma cells, it increased the rate of apoptosis.


CONCLUSIONS
Reduced BAG-1 expression specifically targets tumor cells to apoptosis and impairs tumorigenesis. Our data implicate BAG-1 as a key player in oncogenic transformation by Raf and identify it as a potential molecular target for cancer treatment.
Götz
Rudolf
R
Institut für Medizinische Strahlenkunde und Zellforschung, Universität Würzburg, Germany. goetz@mail.uni-wuerzburg.de
Kramer
Boris W
BW
Camarero
Guadalupe
G
Rapp
Ulf R
UR
D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000209:etiology / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006239:Haplotypes / Q000235:genetics*; D006579:Heterozygote; D008168:Lung / Q000737:chemistry / Q000378:metabolism; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000209:etiology / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors
C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D014157:Transcription Factors; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases