Oncogenic potential of TASK3 (Kcnk9) depends on K+ channel function.
TASK3 gene (Kcnk9) is amplified and overexpressed in several types of human carcinomas. In this report, we demonstrate that a point mutation (G95E) within the consensus K+ filter of TASK3 not only abolished TASK3 potassium channel activity but also abrogated its oncogenic functions, including proliferation in low serum, resistance to apoptosis, and promotion of tumor growth. Furthermore, we provide evidence that TASK3G95E is a dominant-negative mutation, because coexpression of the wild-type and the mutant TASK3 resulted in inhibition of K+ current of wild-type TASK3 and its tumorigenicity in nude mice. These results establish a direct link between the potassium channel activity of TASK3 and its oncogenic functions and imply that blockers for this potassium channel may have therapeutic potential for the treatment of cancers.
Pei
Lin
L
Tularik Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. lpei@tularik.com
Wiser
Ofer
O
Slavin
Anthony
A
Mu
David
D
Powers
Scott
S
Jan
Lily Yeh
LY
Hoey
Timothy
T
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002460:Cell Line; D002478:Cells, Cultured; D004594:Electrophysiology; D005347:Fibroblasts / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009369:Neoplasms / Q000209:etiology*; D010957:Plasmids / Q000378:metabolism; D017354:Point Mutation; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D024683:Potassium Channels, Tandem Pore Domain; D018075:RNA, Complementary / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014981:Xenopus
D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; D018075:RNA, Complementary