Critical roles of Pten in B cell homeostasis and immunoglobulin class switch recombination.
Pten is a tumor suppressor gene mutated in human cancers. We used the Cre-loxP system to generate a B cell-specific mutation of Pten in mice (bPten(flox/flox)mice). bPten(flox/flox) mice showed elevated numbers of B1a cells and increased serum autoantibodies. Among B2 cells in bPten(flox/flox) spleens, numbers of marginal zone B (MZB) cells were significantly increased while those of follicular B (FOB) cells were correspondingly decreased. Pten-deficient B cells hyperproliferated, were resistant to apoptotic stimuli, and showed enhanced migration. The survival kinase PKB/Akt was highly activated in Pten-deficient splenic B cells. In addition, immunoglobulin class switch recombination was defective and induction of activation-induced cytidine deaminase (AID) was impaired. Thus, Pten plays a role in developmental fate determination of B cells and is an indispensable regulator of B cell homeostasis.
Suzuki
Akira
A
Department of Molecular Cell Biology, Research Institute for Microbial Disease, Osaka University, Osaka 565-0871, Japan.
Kaisho
Tsuneyasu
T
Ohishi
Minako
M
Tsukio-Yamaguchi
Manae
M
Tsubata
Takeshi
T
Koni
Pandelakis A
PA
Sasaki
Takehiko
T
Mak
Tak Wah
TW
Nakano
Toru
T
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D016175:B-Lymphocyte Subsets; D001402:B-Lymphocytes / Q000502:physiology*; D018858:Germinal Center / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D017578:Immunoglobulin Class Switching; D007136:Immunoglobulins / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D009154:Mutation; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism
D001323:Autoantibodies; D007136:Immunoglobulins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C045073:Cre recombinase; D019426:Integrases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human