Amanda Ewart-Toland1, 9, Paraskevi Briassouli2, 9, John P de Koning1, 8, 9, Jian-Hua Mao1, Jinwei Yuan1, Florence Chan3, Lucy MacCarthy-Morrogh2, Bruce A J Ponder4, Hiroki Nagase5, John Burn6, Sarah Ball6, 8, Maria Almeida6, Spiros Linardopoulos2, 3
& Allan Balmain1, 71
UCSF Comprehensive Cancer Center, University of California, San Francisco, California 94115, USA.
2
The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.
3
Cancer Research UK, Centre for Cancer Therapeutics, The Institute of Cancer Research Haddow's Laboratories, 15 Cotswold Road, Sutton SM2 5NG, UK.
4
Cancer Research UK, Human Cancer Genetics Group, University Department of Oncology, Strangeways Research Laboratories, Worts Causeway, Cambridge CB1 8RN, UK.
5
Roswell Park Cancer Center, Buffalo, New York, USA.
6
Institute of Human Genetics, Newcastle Upon Tyne, NE1 3B2, UK
7
Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, USA.
8
Present addresses: Department of Physiological Chemistry, University Medical Center Utrecht, P.O. Box 85060, 3508 AB Utrecht, The Netherlands (J.P.d.K.); University Hospitals of Leicester NHS Trust, Leicester Royal Infirmatory, Leicester LE1 5WW, UK (S.B.).
9
These authors contributed equally to this work.
Correspondence should be addressed to Spiros Linardopoulos spiros@icr.ac.uk or Allan Balmain abalmain@cc.ucsf.edu
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 F1 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.
