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Cbl and Cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance.
Zutshi, Neha; Mohapatra, Bhopal C; Mondal, Pinaki; An, Wei; Goetz, Benjamin T; Wang, Shuo; Li, Sicong; Storck, Matthew D; Mercer, David F; Black, Adrian R; Thayer, Sarah P; Black, Jennifer D; Lin, Chi; Band, Vimla; Band, Hamid.
Afiliación
  • Zutshi N; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Mohapatra BC; Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Mondal P; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • An W; Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Goetz BT; Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Wang S; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Li S; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Storck MD; Department of Radiation Oncology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Mercer DF; Department of Radiation Oncology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Black AR; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Thayer SP; Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Black JD; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Lin C; Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Band V; Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Band H; Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
iScience ; 27(6): 109912, 2024 Jun 21.
Article en En | MEDLINE | ID: mdl-38974465
ABSTRACT
Receptor tyrosine kinases (RTKs) control stem cell maintenance vs. differentiation decisions. Casitas B-lineage lymphoma (CBL) family ubiquitin ligases are negative regulators of RTKs, but their stem cell regulatory roles remain unclear. Here, we show that Lgr5+ intestinal stem cell (ISC)-specific inducible Cbl-knockout (KO) on a Cblb null mouse background (iDKO) induced rapid loss of the Lgr5 Hi ISCs with transient expansion of the Lgr5 Lo transit-amplifying population. LacZ-based lineage tracing revealed increased ISC commitment toward enterocyte and goblet cell fate at the expense of Paneth cells. Functionally, Cbl/Cblb iDKO impaired the recovery from radiation-induced intestinal epithelial injury. In vitro, Cbl/Cblb iDKO led to inability to maintain intestinal organoids. Single-cell RNA sequencing in organoids identified Akt-mTOR (mammalian target of rapamycin) pathway hyperactivation upon iDKO, and pharmacological Akt-mTOR axis inhibition rescued the iDKO defects. Our results demonstrate a requirement for Cbl/Cblb in the maintenance of ISCs by fine-tuning the Akt-mTOR axis to balance stem cell maintenance vs. commitment to differentiation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: IScience Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: IScience Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos