| First Author | Krishnan S | Year | 2012 |
| Journal | Blood | Volume | 119 |
| Issue | 17 | Pages | 3951-61 |
| PubMed ID | 22378847 | Mgi Jnum | J:183763 |
| Mgi Id | MGI:5319243 | Doi | 10.1182/blood-2011-05-355602 |
| Citation | Krishnan S, et al. (2012) p85beta regulatory subunit of class IA PI3 kinase negatively regulates mast cell growth, maturation, and leukemogenesis. Blood 119(17):3951-61 |
| abstractText | We show that loss of p85alpha inhibits the growth and maturation of mast cells, whereas loss of p85beta enhances this process. Whereas restoring the expression of p85alpha in P85alpha(-/-) cells restores these functions, overexpression of p85beta has the opposite effect. Consistently, overexpression of p85beta in WT mast cells represses KIT-induced proliferation and IL-3-mediated maturation by inhibiting the expression of Microphthalmia transcription factor. Because p85alpha and p85beta differ in their N-terminal sequences, chimeric proteins consisting of amino or carboxy-terminal of p85alpha and/or p85beta do not rescue the growth defects of p85alpha(-/-) cells, suggesting cooperation between these domains for normal mast cell function. Loss of p85beta impaired ligand induced KIT receptor internalization and its overexpression enhanced this process, partly because of increased binding of c-Cbl to p85beta relative to p85alpha. In vivo, loss of p85beta resulted in increased mast cells, and bone marrow transplantation of cells overexpressing p85beta resulted in significant reduction in some tissue mast cells. Overexpression of p85beta suppressed the growth of oncogenic KIT-expressing cells in vitro and prolonged the survival of leukemic mice in vivo. Thus, p85alpha and p85beta differentially regulate SCF and oncogenic KIT-induced signals in myeloid lineage-derived mast cells. |
