期刊
CELL REPORTS
卷 15, 期 9, 页码 1893-1900出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.04.076
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资金
- Cancer Research Society (CRS)
- Canadian Cancer Society Research Institute (CCSRI) [700525/702500, 702778]
- Canadian Institutes of Health Research/Fonds de la recherche en sante du Quebec (CIHR/FRSQ) of the McGill Integrated Cancer Research Training Program (MICRTP) [FRN53888]
- Canderel award
- George G. Harris award
- Biochemistry Graduate Excellence studentship award
- FRSQ
- CIHR Doctoral Research Award
Endosomal sorting complexes required for transport (ESCRT) drive cell surface receptor degradation resulting in attenuation of oncogenic signaling and pointing to a tumor suppressor function. Here, we show that loss of function of an ESCRT protein (HD-PTP encoded by the PTPN23 gene, located on the tumor suppressor gene cluster 3p21.3) drives tumorigenesis in vivo. Indeed, Ptpn23(+/-) loss predisposes mice to sporadic lung adenoma, B cell lymphoma, and promotes Myc-driven lymphoma onset, dissemination, and aggressiveness. Ptpn23(+/-) derived tumors exhibit an unaltered remaining allele and maintain 50% of HD-PTP expression. Consistent with the role of HD-PTP in attenuation of integrin recycling, cell migration, and invasion, hemizygous Ptpn23(+/-) loss increases integrin beta 1-dependent B cell lymphoma survival and dissemination. Finally, we reveal frequent PTPN23 deletion and downregulation in human tumors that correlates with poor survival. Altogether, we establish HD-PTP/PTPN23 as a prominent haploinsufficient tumor suppressor gene preventing tumor progression through control of integrin trafficking.
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