Tumor suppression by phospholipase C-beta3 via SHP-1-mediated dephosphorylation of Stat5.

Abstract

Given its catalytic activity to generate diacylglycerol and inositol 1,4,5-trisphosphate, phospholipase C (PLC) is implicated in promoting cell growth. However, we found that PLC-beta3-deficient mice develop myeloproliferative disease, lymphoma, and other tumors. The mutant mice have increased numbers of hematopoietic stem cells with increased proliferative, survival, and myeloid-differentiative abilities. These properties are dependent on Stat5 and can be antagonized by the protein phosphatase SHP-1. Stat5-dependent cooperative transformation by active c-Myc and PLC-beta3 deficiency was suggested in mouse lymphomas in PLC-beta3(-/-) and in Emicro-myc;PLC-beta3(+/-) mice and human Burkitt's lymphoma cells. The same mechanism for malignant transformation seems to be operative in other human lymphoid and myeloid malignancies. Thus, PLC-beta3 is likely a tumor suppressor.

• Authors: Wenbin Xiao, Hong Hong, Yuko Kawakami, Yuko Kato, Dianqing Wu, Hiroki Yasudo, Akiko Kimura, Hiromi Kubagawa, Luigi F Bertoli, Randall S Davis, Luan A Chau, Joaquin Madrenas, Cyrus C Hsia, Anargyros Xenocostas, Thomas J Kipps, Lothar Hennighausen, Atsushi Iwama, Hiromitsu Nakauchi, Toshiaki Kawakami
• Journal: Cancer cell (Cancer Cell) Vol. 16 Issue 2 Pg. 161-71 (Aug 04 2009) ISSN: 1878-3686 [Electronic] United States
• PMID: 19647226 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-myc
• STAT5 Transcription Factor
• Tumor Suppressor Proteins
• Protein Tyrosine Phosphatase, Non-Receptor Type 6
• Ptpn6 protein, mouse
• Phospholipase C beta

Topics

• Animals
• Cell Differentiation
• Cell Survival (genetics)
• Cell Transformation, Neoplastic (genetics)
• Hematopoietic Stem Cells (metabolism, pathology)
• Lymphoma (genetics, metabolism, pathology)
• Mice
• Mutation
• Myeloproliferative Disorders (genetics, metabolism, pathology)
• Phospholipase C beta (genetics, metabolism, physiology)
• Phosphorylation
• Protein Tyrosine Phosphatase, Non-Receptor Type 6 (genetics, metabolism, physiology)
• Proto-Oncogene Proteins c-myc (genetics, metabolism, physiology)
• STAT5 Transcription Factor (genetics, metabolism, physiology)
• Signal Transduction
• Tumor Suppressor Proteins (genetics, metabolism, physiology)