tailieunhanh - Báo cáo khoa học: Silencing the constitutive active transcription factor CREB by the LKB1-SIK signaling cascade

Cyclic AMP responsive element (CRE)-binding protein (CREB) is known to activate transcription when its Ser133 is phosphorylated. Two independ-ent investigations have suggested the presence of Ser133-independent acti-vation. One study identified a kinase, salt-inducible kinase (SIK), which repressed CREB; the other isolated a novel CREB-specific coactivator, transducer of regulated CREB activity (TORC), which upregulated CREB activity. | iFEBS Journal Silencing the constitutive active transcription factor CREB by the LKB1-SIK signaling cascade Yoshiko Katoh1 Hiroshi Takemori2 Xing-zi Lin1 Mitsuhiro Tamura1 Masaaki Muraoka3 Tomohiro Satoh3 Yuko Tsuchiya4 Li Min1 Junko Doi5 Akira Miyauchi3 Lee A. Witters6 Haruki Nakamura4 and Mitsuhiro Okamoto7 1 Molecular PhysiologicalChemistry Osaka University MedicalSchool Japan 2 Laboratory of Cell Signaling and Metabolism NationalInstitute of BiomedicalInnovation Osaka Japan 3 ProteinExpress Co. Ltd Chiba Japan 4 Institute for Protein Research Osaka University Japan 5 Food and Nutrition Senri Kinran University Osaka Japan 6 Departments of Medicine and Biochemistry Dartmouth College Hanover NH USA 7 Department of Food and Nutrition Tezukayama University Nara Japan Keywords cAMP responsive element CRE-binding protein LKB1 salt-inducible kinase transducer of regulated CREB activity Correspondence H. Takemori Laboratory of CellSignaling and Metabolism NationalInstitute of BiomedicalInnovation 7-6-8 Asagi Saito Ibaraki Osaka 567-0085 Japan Fax 81 72 641 9836 Tel 81 72 641 9834 E-mail takemori@ Received 16 January 2006 revised 19 April 2006 accepted 24 April 2006 doi Cyclic AMP responsive element CRE -binding protein CREB is known to activate transcription when its Ser133 is phosphorylated. Two independent investigations have suggested the presence of Ser133-independent activation. One study identified a kinase salt-inducible kinase SIK which repressed CREB the other isolated a novel CREB-specific coactivator transducer of regulated CREB activity TORC which upregulated CREB activity. These two opposing signals are connected by the fact that SIK phosphorylates TORC and induces its nuclear export. Because LKB1 has been reported to be an upstream kinase of SIK we used LKB1-defective HeLa cells to further elucidate TORC-dependent CREB activation. In the absence of LKB1 SIK was unable to phosphorylate TORC which led to .