TAILIEUCHUNG - Báo cáo Y học: ATP stimulates MDM2-mediated inhibition of the DNA-binding function of E2F1

Murine double minute 2 (MDM2) protein exhibits many diverse biochemi-cal functions on the tumour suppressor protein p53, including transcrip-tional suppression and E3 ubiquitin ligase activity. However, more recent data have shown that MDM2 can exhibit ATP-dependent molecular chap-erone activity and directly mediate folding of the p53 tetramer. Analysing the ATP-dependent function of MDM2 will provide novel insights into the evolution and function of the protein. | ỊFEBS Journal ATP stimulates MDM2-mediated inhibition of the DNA-binding function of E2F1 Craig Stevens1 z Susanne Pettersson1 Bartosz Wawrzynow1 Maura Wallace2 Kathryn Ball1 Alicja Zylicz3 and Ted R. Hupp1 1 Cell Signaling Unit University of Edinburgh UK 2 RoyalDick Schoolof Veterinary Studies Easter Bush Veterinary Centre Edinburgh UK 3 InternationalInstitute of Molecular and CellBiology in Warsaw Poland Keywords ATP chaperone E2F MDM2 p53 Correspondence T. R. Hupp Institute of Genetics and Molecular Medicine Cell Signalling Unit CRUK p53 SignalTransduction Group University of Edinburgh Edinburgh EH4 2XR UK Fax 44 131 777 3542 Tel 44 131 777 3583 E-mail These authors contributed equally to this paper Received 19 May 2008 revised 16 July 2008 accepted 4 August 2008 doi Murine double minute 2 MDM2 protein exhibits many diverse biochemical functions on the tumour suppressor protein p53 including transcriptional suppression and E3 ubiquitin ligase activity. However more recent data have shown that MDM2 can exhibit ATP-dependent molecular chaperone activity and directly mediate folding of the p53 tetramer. Analysing the ATP-dependent function of MDM2 will provide novel insights into the evolution and function of the protein. We have established a system to analyse the molecular chaperone function of MDM2 on another of its target proteins the transcription factor E2F1. In the absence of ATP MDM2 was able to catalyse inhibition of the DNA-binding function of E2F1. However the inhibition of E2F1 by MDM2 was stimulated by ATP and mutation of the ATP-binding domain of MDM2 K454A prevented the ATP-stimulated inhibition of E2F1. Further ATP stabilized the binding of E2F1 to MDM2 using conditions under which ATP destabilized the MDM2 p53 complex. However the ATP-binding mutant of MDM2 was as active as an E3 ubiquitin ligase on E2F1 and p53 highlighting a specific function for the ATP-binding domain of MDM2 in altering .

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