Transforming activity of Fbxo7 is mediated specifically through regulation of cyclin D/cdk6

Abstract

D cyclins (D1, D2 and D3) and their catalytic subunits (cyclin-dependent kinases cdk4 and cdk6) have a facilitating, but nonessential, role in cell cycle entry. Tissue-specific functions for D-type cyclins and cdks have been reported; however, the biochemical properties of these kinases are indistinguishable. We report that an F box protein, Fbxo7, interacted with cellular and viral D cyclins and distinguished among the cdks that bind D-type cyclins, specifically binding cdk6, in vitro and in vivo. Fbxo7 specifically regulated D cyclin/cdk6 complexes: Fbxo7 knockdown decreased cdk6 association with cyclin and its overexpression increased D cyclin/cdk6 activity and E2F activity. Fbxo7 interacted with p27, but its enhancement of cyclin D/cdk6 activity was p21/p27 independent. Fbxo7 overexpression transformed murine fibroblasts, rendering them tumorigenic in athymic nude mice. Transformed phenotypes were dependent on cdk6, as knockdown of cdk6 reversed them. Fbxo7 was highly expressed in epithelial tumors, but not in normal tissues, suggesting that it may have a proto-oncogenic role in human cancers.

Genetic Loci Implicated in Erythroid Differentiation and Cell Cycle Regulation Are Associated With Red Blood Cell Traits

“…In the mouse, FBXO7 associates specifically with CDK6 to promote CDK6 -cyclin D complex formation and cellular transformation. 52 The effect of trait-associated alleles may be exerted by multiple mechanisms influencing gene expression. 16 Of the SNPs associated with RBC traits in the present study, 15 SNPs in 7 loci were associated with 27 distant eQTLs (Supplemental Table 5, available online at http://www.mayoclinicproceedings.…”

A Competitive Binding Mechanism between Skp1 and Exportin 1 (CRM1) Controls the Localization of a Subset of F-box Proteins

“…Fbxo7 is remarkable in that it operates as a conventional SCF adaptor, stimulating ubiquitination of proteins substrates (which include hepatoma up-regulated protein (HURP) and cellular inhibitor of apoptosis 1 (cIAP1) (12,13)), and also as a selective stabilizer of other interacting proteins. Fbxo7 can enhance the assembly of cyclin D/Cdk6 complexes and augment Cdk6 activity (10,14). It is this property of Fbxo7 that enables it to transform immortalized murine fibroblasts, which are capable of forming tumors when injected into athymic nude mice.…”

“…It is this property of Fbxo7 that enables it to transform immortalized murine fibroblasts, which are capable of forming tumors when injected into athymic nude mice. Fbxo7 may also be a human proto-oncogene, and it has been shown to be overexpressed in various human cancers including lung and colon carcinomas (10). In addition to increases in its expression level, the mislocalization of Fbxo7 may also contribute to its role in cancer.…”

“…Autosomal recessive mutations in FBXO7 have been identified as causing an early-onset Parkinsonian disease (9,11), and Fbxo7 has also been found to be highly expressed in human malignancies (10). We cloned Fbxo7 in a yeast two hybrid screen for proteins interacting with viral D-type cyclins (10).…”

“…Autosomal recessive mutations in FBXO7 have been identified as causing an early-onset Parkinsonian disease (9,11), and Fbxo7 has also been found to be highly expressed in human malignancies (10). We cloned Fbxo7 in a yeast two hybrid screen for proteins interacting with viral D-type cyclins (10). Fbxo7 is remarkable in that it operates as a conventional SCF adaptor, stimulating ubiquitination of proteins substrates (which include hepatoma up-regulated protein (HURP) and cellular inhibitor of apoptosis 1 (cIAP1) (12,13)), and also as a selective stabilizer of other interacting proteins.…”