Pathogenic Role of the CRL4 Ubiquitin Ligase in Human Disease

Abstract

The cullin 4-RING ubiquitin ligase (CRL4) family employs multiple DDB1-CUL4 associated factors substrate receptors to direct the degradation of proteins involved in a wide spectrum of cellular functions. Aberrant expression of the cullin 4A (CUL4A) gene is found in many tumor types, while mutations of the cullin 4B (CUL4B) gene are causally associated with human X-linked mental retardation. This focused review will summarize our current knowledge of the two CUL4 family members in the pathogenesis of human malignancy and neuronal disease, and discuss their potential as new targets for cancer prevention and therapeutic intervention.

Keywords: CRL; CUL4A; CUL4B; cancer; cullin; disease.

Figure 1

Schematic diagram of the multimeric CRL ubiquitin ligase complex. The elongated cullin scaffold binds cullin-specific adaptors (CA) at the N-terminus to recruit substrates (S). All cullins except CUL3 require separate substrate receptors (SR) to bridge the adaptor–substrate interaction. RING protein adaptors (R) bind the ubiquitin (Ub)-charged E2 conjugating enzyme at the cullin C-terminus. Nedd8 post-translational modification (N) promotes cullin activity.