Dataset Information

CDK16 and CDK18 inhibition suppresses nuclear pore-mediated DNA repair and hepatocellular carcinoma [liver tumor]

ABSTRACT: Inhibition of cyclin-dependent kinases (CDK) 4 and 6 has become part of the current standard-of-care treatment in advanced estrogen receptor-positive breast cancer. However, many tumor types are resistant to current CDK inhibitors and the therapeutic value of other CDK family members remains to be validated. By using gene-editing techniques in human cancer cells and genetically-modified mouse models we report here that MYC and beta-catenin driven hepatocellular carcinoma (HCC) is sensitive to the inactivation of CDK16 and CDK18. Whereas individual ablation of CDK14-18 subfamily members displays little effect, concomitant genetic ablation or pharmacological inhibition of CDK16 and CDK18 results in proliferative arrest accompanied by DNA damage and apoptotic cell death. Mechanistically, these defects are associated with a novel role of these proteins in maintaining nuclear pore integrity and the regulation of nucleocytoplasmatic transport. Cyclin Y-CDK16/18 complexes directly phosphorylate the nuclear pore complex (NPC) components NUP35 and NUP214. CDK16/18 inhibition leads to defective nuclear accumulation of the DNA recombinase RAD51, altering DNA repair and inducing lethal levels of DNA damage. Genetic ablation of Cdk16 and Cdk18 in vivo triggers DNA damage and apoptotic cell death in murine liver tumors induced by MYC and -catenin, resulting in tumor regression. Collectively, these data support the development of CDK16/18-targeted therapies for the treatment of HCC.

ORGANISM(S): Mus musculus

PROVIDER: GSE300751 | GEO | 2026/03/10

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Cyclin C was cloned as a growth-promoting G1 cyclin, and several studies postulated a role for cyclin C in driving cell proliferation. Moreover, cyclin C, together with its kinase partner, the cyclin-dependent kinase CDK8, is believed to represent an essential component of basal transcriptional machinery where it globally represses gene expression. However, the function of cyclin C in vivo has never been addressed. Here we show that in the living organism cyclin C acts as a haploinsufficient tumor suppressor, through its function of controlling Notch1 oncogene levels. Cyclin C activates an M-bM-^@M-^\orphanM-bM-^@M-^] CDK19 kinase, as well as CDK8 and CDK3. These cyclin C-CDK complexes phosphorylate Notch1 intracellular domain (ICN1), which allows binding of ICN1 to Fbw7 and triggers ICN1 polyubiquitination. Genetic ablation of cyclin C blocks ICN1 phosphorylation, disrupts Fbw7 binding, and decreases ICN1 ubiquitination in vivo, thereby strongly elevating ICN1 levels in several compartments of cyclin C knockout mice. Ablation of cyclin C, or cyclin C heterozygosity collaborate with other oncogenic lesions and accelerate development of T-cell acute lymphoblastic leukemia (T-ALL) in cyclin Cdeficient mice. Furthermore, the locus encoding cyclin C is heterozygously deleted in a significant fraction of human T-ALL, and these tumors express reduced cyclin C levels. In addition, we describe point mutations in human T-ALL tumors that render cyclin C-CDK unable to phosphorylate ICN1. These studies reveal that in sharp contrast to all other cyclin proteins, cyclin C functions as a growth-suppressor in vivo, and suggest that human tumor cells develop different strategies to evade cyclin C inhibitory function. Comparison of wild-type mouse embryonic fibroblasts (n=3 biological replicates) versus cyclin C knockout MEFs (n=3), wild-type mouse embryonic stem cells (n=3) versus cyclin C knockout ESC (n=3), wild-type mouse embryonic brain (n=3) versus cyclin C knockout embryonic brain (n=3)

Project description:Cyclin C was cloned as a growth-promoting G1 cyclin1,2, and several studies postulated a role for cyclin C in driving cell proliferation3-8 . Moreover, cyclin C, together with its kinase partner, the cyclin-dependent kinase CDK8, is believed to represent an essential component of basal transcriptional machinery where it globally represses gene expression9-13. However, the function of cyclin C in vivo has never been addressed. Here we show that in the living organism cyclin C acts as a haploinsufficient tumor suppressor, through its function of controlling Notch1 oncogene levels. Cyclin C activates an “orphan” CDK19 kinase14, as well as CDK8 and CDK3. These cyclin C-CDK complexes phosphorylate Notch1 intracellular domain (ICN1), which allows binding of ICN1 to Fbw7 and triggers ICN1 polyubiquitination. Genetic ablation of cyclin C blocks ICN1 phosphorylation, disrupts Fbw7 binding, and decreases ICN1 ubiquitination in vivo, thereby strongly elevating ICN1 levels in several compartments of cyclin C knockout mice. Cyclin C was cloned as a growth-promoting G1 cyclin1,2, and several studies postulated a role for cyclin C in driving cell proliferation3-8 . Moreover, cyclin C, together with its kinase partner, the cyclin-dependent kinase CDK8, is believed to represent an essential component of basal transcriptional machinery where it globally represses gene expression9-13. However, the function of cyclin C in vivo has never been addressed. Here we show that in the living organism cyclin C acts as a haploinsufficient tumor suppressor, through its function of controlling Notch1 oncogene levels. Cyclin C activates an “orphan” CDK19 kinase14, as well as CDK8 and CDK3. These cyclin C-CDK complexes phosphorylate Notch1 intracellular domain (ICN1), which allows binding of ICN1 to Fbw7 and triggers ICN1 polyubiquitination. Genetic ablation of cyclin C blocks ICN1 phosphorylation, disrupts Fbw7 binding, and decreases ICN1 ubiquitination in vivo, thereby strongly elevating ICN1 levels in several compartments of cyclin C knockout mice.

Dataset Information

CDK16 and CDK18 inhibition suppresses nuclear pore-mediated DNA repair and hepatocellular carcinoma [liver tumor]

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets