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RISS 인기검색어
- 검색키워드
- 저자 : Ze'ev Ronai (검색결과 2 건)
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TIP49b, a Regulator of Activating Transcription Factor 2 Response to Stress and DNA Damage
Cho, Ssang-Goo,Anindita Bhoumik,Ze'ev Ronai 이화여자대학교 세포신호전달연구센터 2002 고사리 세포신호전달 심포지움 Vol. No.4
Activating transcription factor-2(ATF2/CRE-BP1) is a member of the ATF-CREB family of transcription factors, which has been implicated in growth control, cell cycle progression, differentiation and transformation. Upon exposure to stress or DNA damage, JNK/p38 kinases phosphorylate T-69 and T-71, alleviating intrinsic inhibition and rendering ATF2 transcriptionally active. As a leucine zipper transcription factor, ATF2 binds an 8-bp response element(CRE/URE; 5-TGACGTCA-3; 61), as a homodimer or as a heterodimer with other members of the ATF family, as well as the Jun/Fos family of transcription factors. Although ATF-2 has been implicated in the transcriptional control of various stress-responsive genes, including c-jun, interferon-b, TGFb, and TNFa, our understanding of the biological functions of ATF2 is limited. A yeast two-hybrid screen identified TBP-interacting protein 49b(TIP49b), a component of the INO80 chromatin-remodeling complex, as a novel ATF2-interacting protein. TIP49b's association with ATF2 is phosphorylation dependent and requires amino acids 150 to 248 of ATF2(ATF2^(150-248)), which are implicated in intramolecular inhibition of ATF2 transcriptional activities. Forced expression of TIP49b efficiently attenuated ATF2 transcriptional activities under normal growth conditions as well as after UV treatment, ionizing irradiation, or activation of p38kinase, all of which induced ATF2 phosphorylation and increased TIP49b-ATF2 association. Constitutive expression of ATF2^(150-248) peptide outcompeted TIP49b interaction with ATF2 and alleviated the suppression of ATF2 transcriptional activities. Expression of ATF2^(150-248) in fibroblasts or melanoma but not in ATF2-null cells caused a profound G2M arrest and increased degree of apoptosis following irradiation. The interaction between ATF2 and TIP49b constitutes a novel mechanism that serves to limit ATF2 transcriptional activities and highlights the central role of ATF2 in the control of the cell cycle and apoptosis in response to stress and DNA damage.
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Lau, E.,Kluger, H.,Varsano, T.,Lee, K.,Scheffler, I.,Rimm, David L.,Ideker, T.,Ronai, Ze'ev A. Cell Press ; MIT Press 2012 Cell Vol.148 No.3
The transcription factor ATF2 elicits oncogenic activities in melanoma and tumor suppressor activities in nonmalignant skin cancer. Here, we identify that ATF2 tumor suppressor function is determined by its ability to localize at the mitochondria, where it alters membrane permeability following genotoxic stress. The ability of ATF2 to reach the mitochondria is determined by PKCε, which directs ATF2 nuclear localization. Genotoxic stress attenuates PKCε effect on ATF2; enables ATF2 nuclear export and localization at the mitochondria, where it perturbs the HK1-VDAC1 complex; increases mitochondrial permeability; and promotes apoptosis. Significantly, high levels of PKCε, as seen in melanoma cells, block ATF2 nuclear export and function at the mitochondria, thereby attenuating apoptosis following exposure to genotoxic stress. In melanoma tumor samples, high PKCε levels associate with poor prognosis. Overall, our findings provide the framework for understanding how subcellular localization enables ATF2 oncogenic or tumor suppressor functions.
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