F-box proteins Pof3 and Pof1 regulate Wee1 degradation and mitotic entry in fission yeast

Abstract

The key cyclin-dependent kinase Cdk1 (Cdc2) promotes irreversible mitotic entry, mainly by activating the phosphatase Cdc25 while suppressing the tyrosine kinase Wee1. Wee1 needs to be downregulated at the onset of mitosis to ensure rapid activation of Cdk1. In human somatic cells, one mechanism of suppressing Wee1 activity is mediated by ubiquitylation-dependent proteolysis through the Skp1/Cul1/F-box protein (SCF) ubiquitin E3 ligase complex. This mechanism is believed to be conserved from yeasts to humans. So far, the best-characterized human F-box proteins involved in recognition of Wee1 are β-TrCP (BTRCP) and Tome-1 (CDCA3). Although fission yeast Wee1 was the first identified member of its conserved kinase family, the F-box proteins involved in recognition and ubiquitylation of Wee1 have not been identified in this organism. In this study, our screen using Wee1- luciferase as the reporter revealed that two F-box proteins, Pof1 and Pof3, are required for downregulating Wee1 and are possibly responsible for recruiting Wee1 to SCF. Our genetic analyses supported a functional relevance between Pof1 and Pof3 and the rate of mitotic entry, and Pof3 might play a major role in this process.

Prognostic value of CDCA3 in kidney renal papillary cell carcinoma

“…As shown in Figure 3A , CDCA3 and its related DEGs are involved several diverse biological processes, such as nuclear division and mitotic nuclear division. Qiu [ 42 ] reported that CDCA3 is involved in cell mitosis, validating our results. A GSEA indicated that CDCA3 is related to various gene sets, such as E2F targets, spindle formation during mitosis, KRAS signaling, and G2M checkpoints ( Figure 4 ).…”

“…E2F4 promotes proliferation and cell cycle progression in hepatocellular carcinoma cells by up-regulating CDCA3 expression [ 43 ]. Numerous studies have shown that CDCA3 is related to cell mitosis [ 36 , 42 ]. These results confirmed the results of the GSEA in present study.…”

Long noncoding RNA SNHG12 promotes tumour progression and sunitinib resistance by upregulating CDCA3 in renal cell carcinoma

“…Published articles about CDCA3 mainly focused on the role of CDCA3 in cell cycle regulation and drug resistance in digestive tumours and lung cancer 24,41 . It has been reported that CDCA3 functions as an F-box protein that leads to the ubiquitylation-dependent proteolysis of Wee1 and ultimately results in irreversible mitotic entry 42 . In our research, we found for the first time that CDCA3 upregulated by SNHG12/SP1 was related to RCC and was involved in sunitinib resistance.…”

Synthetic and Medicinal Chemistry Approaches Toward WEE1 Kinase Inhibitors and Its Degraders

“…During M-phase, ubiquitin-dependent protein degradation is responsible for the downfall of WEE1. Initially, during the G2-M transition, PLK1, CDK1, and CK2 phosphorylation at S53, S123, and S121 residues generate phosphodegrons (PDs), and CDC34 ubiquitination of WEE1 allows SCF (skp1/cul1/F-box) β-TrCP (β-transduction repeat-containing protein), Tome-1 (trigger-of-mitotic-entry 1), Smurf1 (Smad ubiquitination regulatory factor1), and Pof1/3 (Promoter of Filamentation1/3) (in fission yeast) mediated WEE1 degradation. − However, in a later study, WEE1 was found to interact with the β-subunit of CK2, but this interaction showed no remarkable influence on WEE1 kinase activity . Another mechanism reported is the nuclear export of WEE1.…”