Notch and the pre-TCR coordinate thymocyte proliferation by induction of the SCF subunits Fbxl1 and Fbxl12.
Nat Immunol
; 20(10): 1381-1392, 2019 10.
Article
en En
| MEDLINE
| ID: mdl-31451788
ABSTRACT
Proliferation is tightly regulated during T cell development, and is limited to immature CD4-CD8- thymocytes. The major proliferative event is initiated at the 'ß-selection' stage following successful rearrangement of Tcrß, and is triggered by and dependent on concurrent signaling by Notch and the pre-T cell receptor (TCR); however, it is unclear how these signals cooperate to promote cell proliferation. Here, we found that ß-selection-associated proliferation required the combined activity of two Skp-cullin-F-box (SCF) ubiquitin ligase complexes that included as substrate recognition subunits the F-box proteins Fbxl1 or Fbxl12. Both SCF complexes targeted the cyclin-dependent kinase inhibitor Cdkn1b for polyubiquitination and proteasomal degradation. We found that Notch signals induced the transcription of Fbxl1, whereas pre-TCR signals induced the transcription of Fbxl12. Thus, concurrent Notch and pre-TCR signaling induced the expression of two genes, Fbxl1 and Fbxl12, whose products functioned identically but additively to promote degradation of Cdkn1b, cell cycle progression, and proliferation of ß-selected thymocytes.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Linfocitos T
/
Receptores de Antígenos de Linfocitos T alfa-beta
/
Proteínas Ligasas SKP Cullina F-box
/
Proteínas F-Box
/
Receptores Notch
/
Timocitos
Límite:
Animals
Idioma:
En
Año:
2019
Tipo del documento:
Article