12-O-tetradecanoylphorbol-Manganese superoxide dismutase (MnSOD) 4 is a nuclearencoded antioxidant enzyme that is imported into the mitochondrial matrix (1), to catalyze the dismutation of superoxide radical anions (O 2 . ) into hydrogen peroxide (H 2 O 2 ) and oxygen (2). MnSOD is considered as the primary defensive enzyme against oxidative stress within mitochondria (3). Targeted disruption of murine sod2 causes dilated cardiomyopathy and neonatal lethality (4). In addition, a low level of MnSOD has been implicated in causing various human tumors (5), whereas its overexpression suppresses tumorigenicity (6, 7).A number of studies have demonstrated the induction of MnSOD in various cell lines and tissues following oxidative stress induced by treatments with TNF-␣ (8 -12), interleukin-1 (8, 10 -12), lipopolysaccharide (10, 12), interferon-␥ (11), 12-Otetradecanoylphorbol-13-acetate (TPA) (12, 13), or irradiation (14, 15). The induction of MnSOD is transactivated via two parts of the sod2 gene in various species following oxidative stress. One part is the 5Ј-flanking promoter region regulated by Sp-1 (16 -18), and with early growth response factor (Egr-1) after treatment with TPA (19), or by 17,[20][21][22]. The other part is the enhancer within the second intron regulated by the CCAAT/enhancer-binding protein (C/EBP) and NF-B in response to TNF-␣ and interleukin-1 (IL-1) (23,24) or TPA (25,26). We have previously identified the manganese superoxide dismutase TPA-responsive element (MSTRE), in the 5Ј-flanking region, located between Ϫ1292 and Ϫ1202, which contains a cAMP-responsive element (CRE)-like sequence, and demonstrated that CREB/ATF-1 bound to MSTRE and TPA treatment induced CREB phosphorylation (27).It has been proposed that the tumor-promoting phorbol ester, TPA, (28, 29) induces MnSOD expression in a protein kinase C (PKC)-dependent manner (27, 30 -32). Our previous study using A549 cells reveals that PKC may be involved in CREB phosphorylation (27), and another study has shown that transcription factor FOXO3a (also known as FKHRL1) can elevate the expression of MnSOD in response to oxidative stress (33). In addition, FOXO transcription factors are known to trig-