DNA damage-induced protein 14-3-3 σ inhibits protein kinase B/Akt activation and suppresses Akt-activated cancer

14-3-3 σ is induced by tumor suppressor protein p53 in response to DNA damage. p53 can directly transactivate the expression of 14-3-3 σ to cause a G₂ cell cycle arrest when cell DNA is damaged. The expression of 14-3-3 σ protein is down-regulated in various tumors, but its function has not been fully established. Protein kinase B/Akt, a crucial regulator of oncogenic signal involved in cell survival and proliferation, is deregulated in many types of cancer. Akt activation can enhance p53 degradation, but its role in DNA damage response is not clear. Here, we show that Akt activation is diminished when p53 and 14-3-3 σ is up-regulated in response to DNA damage. Evidence is provided that 14-3-3 σ binds and inhibits Akt. In keeping with this concept, Akt-mediated cell survival is inhibited by 14-3-3 σ. Significantly, we show that 14-3-3 σ inhibits Akt-mediated cell growth, transformation, and tumorigenesis. Low expression of 14-3-3 σ in human primary breast cancers correlates with Akt activation. These data provide an insight into Akt regulation and rational cancer gene therapy by identifying 14-3-3 σ as a molecular regulator of Akt and as a potential anticancer agent for Akt-activated cancers.