Activating transcription factor (ATF)/cAMP-response element (CRE)-binding (CREB) proteins induce the CRE-mediated gene transcription depending on the cAMP stimulation. cAMPdependent signaling oscillates in a circadian manner, which in turn also sustains core oscillation machinery of the circadian clock. Here, we show that among the ATF/CREB family proteins, ATF4 is essential for the circadian expression of the Period2 (Per2) gene, a key component of the circadian clock. Transcription of the Atf4 gene was regulated by core components of the circadian clock, and its expression exhibited circadian oscillation in mouse tissues as well as embryonic fibroblasts. ATF4 bound to the CRE of the Per2 promoter in a circadian time-dependent manner and periodically activated the transcription of the Per2 gene. Consequently, the oscillation of the Per2 expression was attenuated in embryonic cells prepared from Atf4-null mice. Furthermore, the loss of ATF4 also disrupted the rhythms in the expression of other clock genes. These results suggest that ATF4 is a component responsible for sustaining circadian oscillation of CRE-mediated gene expression and also constitute a molecular link connecting cAMP-dependent signaling to the circadian clock.Genetic and molecular approaches have identified a basic mechanism of the circadian oscillator that is governed by interconnected transcriptional and translational feedback loops (1, 2). Gene products of Clock and Bmal1 (also known as Arntl) form a heterodimer that activates the transcription of Period (Per) and Cryptochrome (Cry) genes. Once PER and CRY proteins have reached a critical concentration, they attenuate CLOCK/BMAL1-mediated transactivation, thus generating circadian oscillation in their own transcription. Rev-erb␣ (known as Nrd1d1) is also activated by CLOCK/BMAL1 and transrepressed by PER and CRY, resulting in circadian oscillation in the expression of Rev-erb␣. In turn, REV-ERB␣ periodically represses Bmal1 transcription, thereby interconnecting the positive and negative loops (3). Like the mechanism of Reverb␣ transcription, clock genes comprising the core oscillation loop transduce downstream events by regulating the expression of clock-controlled output genes (4). cAMP-dependent signaling is involved in the circadian output pathways, but the cAMP signaling subsequently sustains the core oscillation loops in the suprachiasmatic nucleus (SCN), 3 the center of the mammalian circadian clock (5, 6). However, the regulation mechanism of cAMP to sustain the circadian oscillator remains to be elucidated.The intracellular accumulation of cAMP induces CRE-mediated gene expression via ATF/CREB protein activation (7). ATF/CREB proteins belong to the bZIP transcription factor superfamily, and they are characterized by a conserved domain including highly charged basic amino acids that are required for DNA recognition at the TGACGT(C/A)(G/A) sequence (8). Although the phosphorylated states of CREB in the SCN vary in a circadian manner (5), the functional importance of the transcriptional...

Many cancers overexpress ATF4, a stress-induced transcription factor that promotes cell survival under hypoxic conditions and other stresses of the tumor microenvironment, but the potential contributions of ATF4 to oncogenesis itself have been little explored. Here, we report that ATF4 promotes oncogene-induced neoplastic transformation by suppressing the expression of cellular senescence-associated genes. Strikingly, primary embryo fibroblasts from ATF4-deficient mice were resistant to transformation by coexpression of H-ras V12 and SV40 large T antigen. In wild-type cells these oncogenes induced expression of the murine Atf4 gene along with the cyclindependent kinase inhibitor Cdkn2a, which encodes the cell senescence-associated proteins p16INK4 and p19ARF. Elevated levels of ATF4 were sufficient to suppress expression of these proteins and drive oncogenic transformation. Conversely, genetic ablation of ATF4 led to constitutive expression of p16INK4a and p19ARF, triggering cellular senescence. Our findings define a central function for ATF4 in promoting oncogenic transformation by suppressing a central pathway of cellular senescence. Cancer Res; 72(2); 395-401. Ó2011 AACR.

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Supplementary Figures 1-5 from Stress-Regulated Transcription Factor ATF4 Promotes Neoplastic Transformation by Suppressing Expression of the INK4a/ARF Cell Senescence Factors

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