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Spatial Distribution and Function of Sterol Regulatory Element-Binding Protein 1a and 2 Homo- and Heterodimers by In Vivo Two-Photon Imaging and Spectroscopy Fluorescence Resonance Energy Transfer

Aikaterini Zoumi,^1, Shrimati Datta,^2, Lih-Huei L. Liaw,¹ Cristen J. Wu,¹ Gopi Manthripragada,^1, Timothy F. Osborne,² and Vickie J. LaMorte^1*

Laser Microbeam and Medical Program, Beckman Laser Institute, Department of Surgery,¹ Department of Molecular Biology and Biochemistry, University of California, Irvine, California²

Received 10 September 2004/ Returned for modification 15 October 2004/ Accepted 4 January 2005

Sterol regulatory element-binding proteins (SREBPs) are a subfamily of basic helix-loop-helix-leucine zipper proteins that regulate lipid metabolism. We show novel evidence of the in vivo occurrence and subnuclear spatial localization of both exogenously expressed SREBP-1a and -2 homodimers and heterodimers obtained by two-photon imaging and spectroscopy fluorescence resonance energy transfer. SREBP-1a homodimers localize diffusely in the nucleus, whereas SREBP-2 homodimers and the SREBP-1a/SREBP-2 heterodimer localize predominantly to nuclear speckles or foci, with some cells showing a diffuse pattern. We also used tethered SREBP dimers to demonstrate that both homo- and heterodimeric SREBPs activate transcription in vivo. Ultrastructural analysis revealed that the punctate foci containing SREBP-2 are electron-dense nuclear bodies, similar or identical to structures containing the promyelocyte (PML) protein. Immunofluorescence studies suggest that a dynamic interplay exists between PML, as well as another component of the PML-containing nuclear body, SUMO-1, and SREBP-2 within these nuclear structures. These findings provide new insight into the overall process of transcriptional activation mediated by the SREBP family.

A.Z. and S.D. contributed equally to this work.

Present address: Department of Medicine, Georgetown University, Washington, D.C.