A novel activation-induced suicidal degradation mechanism for Akt by selenium.
Selenium has been associated with an anti-cancer effect via the modulation of Akt. In order to investigate whether selenium modulates Akt by hitherto unidentified molecular mechanisms, we examined the effect of selenium on the stability and activity of Akt. Selenium induced destabilization of Akt which is coupled to its own enzyme activation. Mutation of T308 and S473 of Akt to alanine as well as the inhibition or depletion of upstream kinases for Akt activation blocked Akt degradation. These features of Akt degradation are reminiscent of the 'activation-induced suicidal degradation' mechanism. PTEN was also required for Akt destabilization as Akt activation alone was unable to elicit Akt degradation in the absence of PTEN. Conversely, PTEN introduction in PTEN-null prostate cancer cells restored the ability to degrade Akt upon selenium treatment. Collectively, selenium seems to achieve ultimate negative regulation of Akt signaling by destabilizing the protein, and this regulation mechanism might provide a paradigm for the anti-cancer activity of selenium.
Lee
Ji-Hyun
JH
Laboratory of Modulation of Radiobiological Responses, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.
Shin
Sun Hye
SH
Kang
Seongman
S
Lee
Yun-Sil
YS
Bae
Sangwoo
S
D000595:Amino Acid Sequence; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004795:Enzyme Stability / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D012643:Selenium / Q000494:pharmacology*
D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; D012643:Selenium