Timothy F. Osborne
Molecular Biology & Biochemistry
School of Biological Sciences
Phone: (949)824-2979
Email: tfosborn@uci.edu
http://www.faculty.uci.edu/profile.cfm?faculty_id=2701
darwin.bio.uci.edu/~osborne/TOindex.html
Timothy Osborne
In mammals there are three members of the sterol regulatory element binding protein (SREBP) family of transcription factors. They activate key genes that encode enzymes of lipid biosynthesis and metabolism but also activate key genes in cell cycle control and apoptosis such as p21 and c-FLIP. SREBP-1a and 1c are encoded by overlapping mRNAs from a single gene and SREBP-2 is transcribed from a distinct gene. SREBPs bind DNA as dimers through their bHLHLZ domains and they have the potential to homo and heterodimerize with one another. SREBP-1a and 1c are produced from the same gene through the use of alternative gene promoters that drive transcription of mRNAs with different 5’ terminal exons. Each unique exon is spliced to a common second exon and from this point on the two coding sequences are identical. This results in proteins that are identical except for their extreme amino termini. These two proteins share over 70 % identity with the SREBP-2 protein.
The SREBP isoforms are expressed in overlapping but distinct patterns. For example, SREBP-1a is expressed widely at a very low level whereas SREBP-1c is expressed at varying levels in different tissues and is highly regulated by insulin and oxysterol signaling in the liver. In contrast, SREBP-2 is expressed widely at low levels but is both auto-regulated and activated by thyroid hormone signaling.
Because of the extensive sequence similarity between the three proteins they perform overlapping functions and it has been difficult to specifically assign a unique biological role for each one. Mouse knockout studies have been performed where both SREBP-1a and 1c were simultaneously inactivated and this results in partial embryonic lethality. In order to have a complete set of knockout models that selectively target each SREBP, Dr. Osborne has focused on the targeted knockout of SREBP-1a. This was accomplished by a gene trapping approach along with assistance through the baygenomics consortium (baygenomics.ucsf.edu). One ES clone had an insertion in the unique SREBP-1a intron was identified. They used the corresponding ES cells to generate a line of mice containing the targeted gene knockout. The homozygous SREBP-1a -/- knockout animal is completely viable and shows ho obvious outward distinguishing physical traits at birth. In initial characterizations in these mice they have shown they have a significant increase in cell proliferation in the small intestinal crypts and hepatocytes. This indicates that SREBP-1a has a key role in regulating cell proliferation, possibly through activation of the p21 protein mentioned above. Interestingly, even though there is increased proliferation, there is no increase in intestinal or hepatocyte cell number. To compensate for the elevated proliferation, there is an increase in apoptosis. Dr. Osborne hypothesizes that the increase in cell proliferation in both the intestine and liver will sensitize the mice to development of hepatocyte and intestinal derived cancers.
Selected Publications:
Zoumi, A., Datta, S., Liaw, L. H., Wu, C. J., Manthripragada, G., Osborne, T. F., and Lamorte, V. J. (2005). 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. Mol Cell Biol 25(8), 2946-56.
Shin, D. J., Plateroti, M., Samarut, J., and Osborne, T. F. (2006). Two uniquely arranged thyroid hormone response elements in the far upstream 5' flanking region confer direct thyroid hormone regulation to the murine cholesterol 7alpha hydroxylase gene. Nucleic Acids Res 34(14), 3853-61.
Datta, S., Wang, L., Moore, D. D., and Osborne, T. F. (2006). Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase promoter by nuclear receptors liver receptor homologue-1 and small heterodimer partner: a mechanism for differential regulation of cholesterol synthesis and uptake. J Biol Chem 281(2), 807-12.
Matsukuma, K. E., Wang, L., Bennett, M. K., and Osborne, T. F. (2007). A key role for orphan nuclear receptor liver receptor homologue-1 in activation of fatty acid synthase promoter by liver X receptor. J Biol Chem 282(28), 20164-71.
Shin, D. J., and Osborne, T. F. (2008). PGC-1alpha activation of CYP7A1 during food restriction and diabetes is still inhibited by sall heterodimer partner. J Biol Chem. |
