Proc Natl Acad Sci U S A. 2003 Jun 2 [Epub ahead of print]
Oncogenic potential of TASK3 (Kcnk9) depends on K+ channel function.
Pei L, Wiser O, Slavin A, Mu D, Powers S, Jan LY, Hoey T.
*Tularik Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080; Department of Neuroscience, University of California, 533 Parnassus Avenue, San Francisco, CA 94143.
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 TASK3(G95E) 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.
Nature. 2003 May 29;423(6939):555-60.
Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors.
Wang Z, Benoit G, Liu J, Prasad S, Aarnisalo P, Liu X, Xu H, Walker NP, Perlmann T.
[1] Department of Structural Biology, Tularik Inc., 1120 Veterans Blvd., South San Francisco, California 94080, USA [2] These authors contributed equally to this work.
Members of the nuclear receptor (NR) superfamily of transcription factors modulate gene transcription in response to small lipophilic molecules. Transcriptional activity is regulated by ligands binding to the carboxy-terminal ligand-binding domains (LBDs) of cognate NRs. A subgroup of NRs referred to as 'orphan receptors' lack identified ligands, however, raising issues about the function of their LBDs. Here we report the crystal structure of the LBD of the orphan receptor Nurr1 at 2.2 A resolution. The Nurr1 LBD adopts a canonical protein fold resembling that of agonist-bound, transcriptionally active LBDs in NRs, but the structure has two distinctive features. First, the Nurr1 LBD contains no cavity as a result of the tight packing of side chains from several bulky hydrophobic residues in the region normally occupied by ligands. Second, Nurr1 lacks a 'classical' binding site for coactivators. Despite these differences, the Nurr1 LBD can be regulated in mammalian cells. Notably, transcriptional activity is correlated with the Nurr1 LBD adopting a more stable conformation. Our findings highlight a unique structural class of NRs and define a model for ligand-independent NR function. |
