An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance.

Autor:	Mohapatra B; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA., Zutshi N; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA., An W; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA., Goetz B; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA., Arya P; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA., Bielecki TA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA., Mushtaq I; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA., Storck MD; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA., Meza JL; Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA., Band V; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA., Band H; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA hband@unmc.edu.; Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Jazyk:	angličtina
Zdroj:	Development (Cambridge, England) [Development] 2017 Mar 15; Vol. 144 (6), pp. 1072-1086. Date of Electronic Publication: 2017 Jan 18.
DOI:	10.1242/dev.138164
Abstrakt:	The ubiquitin ligases CBL and CBL-B are negative regulators of tyrosine kinase signaling with established roles in the immune system. However, their physiological roles in epithelial tissues are unknown. Here, we used MMTV-Cre-mediated Cbl gene deletion on a Cbl-b null background, as well as a tamoxifen-inducible mammary stem cell (MaSC)-specific Cbl and Cbl-b double knockout ( Cbl/Cbl-b DKO) using Lgr5-EGFP-IRES-CreERT2, to demonstrate a mammary epithelial cell-autonomous requirement of CBL and CBL-B in the maintenance of MaSCs. Using a newly engineered tamoxifen-inducible Cbl and Cbl-b deletion model with a dual fluorescent reporter ( Cbl flox/flox ; Cbl-b flox/flox ; Rosa26-CreERT; mT/mG ), we show that Cbl/Cbl-b DKO in mammary organoids leads to hyperactivation of AKT-mTOR signaling with depletion of MaSCs. Chemical inhibition of AKT or mTOR rescued MaSCs from Cbl/Cbl-b DKO-induced depletion. Our studies reveal a novel, cell-autonomous requirement of CBL and CBL-B in epithelial stem cell maintenance during organ development and remodeling through modulation of mTOR signaling. (© 2017. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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