Disease relevance of CUL4A

• TFDP1, CUL4A, and CDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas [1].
• The CUL-4A gene has been shown to be amplified and up-regulated in breast carcinomas [2].
• The xeroderma pigmentosum group E gene product DDB2 is a specific target of cullin 4A in mammalian cells [3].
• CUL-4A encodes one of six mammalian cullins and is amplified and/or overexpressed in breast cancer, which suggests a role in regulating cell cycle progression [4].

High impact information on CUL4A

• Both complexes contain cullin 4A and Roc1 and display ubiquitin ligase activity [5].
• A new NEDD8-ligating system for cullin-4A [6].
• Interfering CUL-4A biosynthesis by ectopic expression or by RNA-mediated interference resulted in alterations of the steady-state levels of HOXA9, mirrored by impairment of the ability of 32D myeloid progenitor cells to undergo proper terminal differentiation into granulocytes [7].
• The UV-DDB complex is a component of the newly identified cullin 4A-based ubiquitin E3 ligase, DDB1-CUL4A(DDB2) [8].
• CUL-4A is critical for early embryonic development [4].

Biological context of CUL4A

• In human cells, inactivation of CUL4A induces CDK inhibitor p27(Kip1) stabilization and G(1) cell cycle arrest which is dependent on the presence of p27, suggesting that this regulatory pathway is evolutionarily conserved [9].
• These findings identify DDB subunits as the first substrates of the CUL-4A ubiquitination machinery and suggest that abnormal expression of Cul-4A results in reduced p48 levels, thus impairing the ability of DDB in lesion recognition and DNA repair in tumor cells [10].
• Despite 87% similarity between the Cul-4A and Cul-4B cullins, the CUL-4A(-/-) lethal phenotype indicates that CUL-4A has one or more distinct function(s) [4].

Anatomical context of CUL4A

• However, CUL-4A(-/-) blastocysts are viable, hatch, form an inner cell mass and trophectoderm, and implant (roughly 4.5 dpc), indicating that CUL-4A(-/-) embryos die between 4.5 and 7.5 dpc [4].

Other interactions of CUL4A

• In conclusion, our findings suggest that TFDP1, CUL4A, and CDC16 are probable targets of an amplification mechanism and therefore may be involved, together or separately, in development and/or progression of some HCCs [1].
• Cullin 4A associates with the UV-damaged DNA-binding protein DDB [2].
• CUL-4A is a member of the cullin family of proteins, which are believed to be ubiquitin-protein isopeptide ligases (type E3) [2].
• Recently we found that NEDD8, a ubiquitin-like protein, was linked covalently to human cullin-4A (abbreviated Cul-4A) by a new ubiquitin-related pathway that is analogous to but distinct from the ligating system for SUMO1, another ubiquitin-like protein [11].
• Unlike HOXA9, the NUP98-HOXA9 fusion was protected from ubiquitination mediated by Cullin-4A and subsequent proteasome-dependent degradation [12].

References