Differential expression of a novel ankyrin containing E3 ubiquitin-protein ligase, Hace1, in sporadic Wilms' tumor versus normal kidney.
We have analyzed the chromosome 6q21 breakpoint of a non-constitutional t(6;15)(q21;q21) rearrangement in sporadic Wilms' tumor. This identified a novel gene encoding a protein with six N-terminal ankyrin repeats linked to a C-terminal HECT ubiquitin-protein ligase domain. We therefore designated this gene HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1). HACE1 is widely expressed in human tissues, including mature and fetal kidney. We show that Hace1 protein possesses intrinsic ubiquitin ligase activity, utilizes UbcH7 as a candidate partner E2 enzyme and localizes predominantly to the endoplasmic reticulum. Although the HACE1 locus was not directly interrupted by the translocation in the index Wilms' case, its expression was markedly lower in tumor tissue compared with adjacent normal kidney. Moreover, HACE1 expression was virtually undetectable in the SK-NEP-1 Wilms' tumor cell line and in four of five additional primary Wilms' tumor cases compared with patient-matched normal kidney. We found no evidence of HACE1 mutations or deletions, but hypermethylation of two upstream CpG islands correlates with low HACE1 expression in tumor samples. Our findings implicate Hace1 as a novel ubiquitin-protein ligase and demonstrate that its expression is very low in primary Wilms' tumors.
Anglesio
Michael S
MS
Department of Pathology, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.
Evdokimova
Valentina
V
Melnyk
Nataliya
N
Zhang
Liyong
L
Fernandez
Conrad V
CV
Grundy
Paul E
PE
Leach
Stephen
S
Marra
Marco A
MA
Brooks-Wilson
Angela R
AR
Penninger
Josef
J
Sorensen
Poul H B
PH
D017089:Ankyrin Repeat / Q000235:genetics; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D019175:DNA Methylation; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D042541:Intracellular Space / Q000737:chemistry / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D009396:Wilms Tumor / Q000201:enzymology* / Q000235:genetics*
D012333:RNA, Messenger; C497506:HACE1 protein, human; D044767:Ubiquitin-Protein Ligases