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Coordinate suppression of B cell lymphoma by PTEN and SHIP
Author(s) -
Miletic Ana V.,
AnzelonMills Amy N.,
Mills David M.,
Omori Sidne A.,
Pedersen Irene M.,
Ravetch Jeffrey V.,
Bolland Silvia,
Rickert Robert C.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.662.12
Subject(s) - pten , lymphoma , cancer research , protein kinase b , pi3k/akt/mtor pathway , mapk/erk pathway , b cell , kinase , biology , microbiology and biotechnology , signal transduction , immunology , antibody
Downstream of the B cell receptor, activation of PI3K results in the generation of phosphatidylinositol‐3,4,5‐trisphosphate (PIP3) and promotes survival and proliferation of B lymphocytes through the activation of proteins including PDK, Akt, TOR, cyclins D and E, and FOXO1. The actions of PI3K are antagonized by the inositol phosphatases, PTEN and SHIP. Whereas deletion of PTEN in T cells causes aggressive T cell lymphomas, loss of PTEN in B lymphocytes does not result in malignancy. Thus, we hypothesized that SHIP compensates for the lack of PTEN in B lymphocytes thereby preventing lymphoma development. To this end, we generated mice lacking both PTEN and SHIP specifically in B lymphocytes (bPTEN/SHIP−/−) and show that bPTEN/SHIP−/− mice develop lethal B‐Non‐Hodgkin's Lymphoma (B‐NHL). Mechanistically, PTEN/SHIP−/− B cells are hyperresponsive to mitogenic stimulation with increased proliferation and mitogen‐activated protein kinase (MAPK) activation. Interestingly, PTEN/SHIP‐deficient B cells also display an atypical mitogenic response to the survival factor BAFF. Taken together, these studies reveal that PTEN and SHIP act cooperatively to suppress B‐NHL and provide the first direct evidence that SHIP can function as a tumor suppressor. This research is supported by a postdoctoral fellowship from the Cancer Research Institute.