Disease relevance of Cul1

• Relatively little is known about the function of the CUL-4A cullin, but its overexpression in breast cancer suggests CUL-4A might also regulate the cell cycle [1].

High impact information on Cul1

• To study the role of Cul-1 in mammalian development and cell-cycle regulation, we generated mice deficient for Cul1 and analysed null embryos and heterozygous cell lines [2].
• Using an in vitro assay for centriole separation in Xenopus extracts, antibodies to Skp1 or Cul1 block separation [3].
• Using immunofluorescence microscopy, we show that in mammalian cells the Skp1 protein and the cullin Cul1 are localized to interphase and mitotic centrosomes and to the cytoplasm and nucleus [3].
• Thus, the NEDD8 system is essential for the regulation of protein degradation pathways involved in cell cycle progression and morphogenesis, possibly through the function of the Cul family proteins [4].
• Overall, the SOCS box and SH2 domain show a conserved spatial domain arrangement with the BC box and substrate recognition domain of the von Hippel-Lindau (VHL) tumor suppressor protein, suggesting a common mechanism of ubiquitination in these cullin-dependent E3 ligases [5].

Biological context of Cul1

• Deletion of the Cul1 gene in mice causes arrest in early embryogenesis and accumulation of cyclin E [6].
• Fbxw8 is essential for Cul1-Cul7 complex formation and for placental development [7].
• Partial inactivation of Cul1 delayed the abrupt loss of E2F immunofluorescence beyond its normal point of downregulation at the onset of S phase [8].
• Cdc53 represents a multigene family, the human homologues of which, the cullin family, include at least six distinct members [9].

Anatomical context of Cul1

• Outgrowths of Cul1(-/-) blastocysts had limited proliferative capacity in vitro and accumulated cyclin E in all cells [6].
• CD40 ligation compensated for CD22 deficiency by restoring lymphoblast development, proliferation, c-Myc and CUL1 expression, and protein ubiquitination/degradation in IgM-stimulated B6 CD22(-/-) B cell cultures [10].

Associations of Cul1 with chemical compounds

• Mercury-containing sulfhydryl modification agents (rho-hydroxymercuribenzoate and mercuric chloride) irreversibly inhibit the ROC1-CUL1 ubiquitin ligase activity without disrupting the complex [11].

Other interactions of Cul1

• SCF ubiquitin ligases, composed of three major subunits, Skp1, Cul1, and one of many F box proteins (Fbps), control the proteolysis of important cellular regulators [12].
• That B6 CD22(-/-) B cells predominantly underwent apoptosis following IgM ligation correlated with this unique tolerant phenotype, as well as defective induction of the c-Myc:Cullin 1 (CUL1) ubiquitin ligase pathway that is necessary for progression to the S phase of cell cycle [10].

References