Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human.
Linkage analysis and haplotype mapping in interspecific mouse crosses (Mus musculus x Mus spretus) identified the gene encoding Aurora2 (Stk6 in mouse and STK15 in human) as a candidate skin tumor susceptibility gene. The Stk6 allele inherited from the susceptible M. musculus parent was overexpressed in normal cells and preferentially amplified in tumor cells from F(1) hybrid mice. We identified a common genetic variant in STK15 (resulting in the amino acid substitution F31I) that is preferentially amplified and associated with the degree of aneuploidy in human colon tumors. The Ile31 variant transforms rat1 cells more potently than the more common Phe31 variant. The E2 ubiquitin-conjugating enzyme UBE2N was a preferential binding partner of the 'weak' STK15 Phe31 variant form in yeast two-hybrid screens and in human cells. This interaction results in colocalization of UBE2N with STK15 at the centrosomes during mitosis. These results are consistent with an important role for the Ile31 variant of STK15 in human cancer susceptibility.
Ewart-Toland
Amanda
A
UCSF Comprehensive Cancer Center, University of California, San Francisco, California 94115, USA.
Briassouli
Paraskevi
P
de Koning
John P
JP
Mao
Jian-Hua
JH
Yuan
Jinwei
J
Chan
Florence
F
MacCarthy-Morrogh
Lucy
L
Ponder
Bruce A J
BA
Nagase
Hiroki
H
Burn
John
J
Ball
Sarah
S
Almeida
Maria
M
Linardopoulos
Spiros
S
Balmain
Allan
A
D000782:Aneuploidy; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002455:Cell Division / Q000235:genetics; D002874:Chromosome Mapping; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D003433:Crosses, Genetic; D005784:Gene Amplification; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D066298:In Vitro Techniques; D008025:Ligases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009115:Muridae; D009857:Oncogenes; D020161:Physical Chromosome Mapping; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics; D020798:Two-Hybrid System Techniques; D044763:Ubiquitin-Conjugating Enzymes
D011994:Recombinant Proteins; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes; C576917:AURKA protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D008025:Ligases