CDK19 regulates the proliferation of hematopoietic stem cells and acute myeloid leukemia cells by suppressing p53-mediated transcription of p21.
Leukemia
; 36(4): 956-969, 2022 04.
Article
de En
| MEDLINE
| ID: mdl-35110726
ABSTRACT
The cell cycle progression of hematopoietic stem cells (HSCs) and acute myeloid leukemia (AML) cells is precisely controlled by multiple regulatory factors. However, the underlying mechanisms are not fully understood. Here, we find that cyclin-dependent kinase 19 (CDK19), not its paralogue CDK8, is relatively enriched in mouse HSCs, and its expression is more significantly increased than CDK8 after proliferative stresses. Furthermore, SenexinB (a CDK8/19 inhibitor) treatment impairs the proliferation and self-renewal ability of HSCs. Moreover, overexpression of CDK19 promotes HSC function better than CDK8 overexpression. Using CDK19 knockout mice, we observe that CDK19-/- HSCs exhibit similar phenotypes to those of cells treated with SenexinB. Interestingly, the p53 signaling pathway is significantly activated in HSCs lacking CDK19 expression. Further investigations show that CDK19 can interact with p53 to inhibit p53-mediated transcription of p21 in HSCs and treatment with a specific p53 inhibitor (PFTß) partially rescues the defects of CDK19-null HSCs. Importantly, SenexinB treatment markedly inhibits the proliferation of AML cells. Collectively, our findings indicate that CDK19 is involved in regulating HSC and AML cell proliferation via the p53-p21 pathway, revealing a new mechanism underlying cell cycle regulation in normal and malignant hematopoietic cells.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Cellules souches hématopoïétiques
/
Leucémie aigüe myéloïde
/
Protéine p53 suppresseur de tumeur
/
Kinases cyclines-dépendantes
Limites:
Animals
/
Humans
Langue:
En
Journal:
Leukemia
Sujet du journal:
HEMATOLOGIA
/
NEOPLASIAS
Année:
2022
Type de document:
Article
Pays d'affiliation:
Chine