Bryce M. Paschal
- Postdoc, The Scripps Research Institute, La Jolla, CA
- BA, University of North Carolina, Chapel Hill, NC
- PhD, University of Massachusetts Medical School, MA
- Professor, Biochemistry and Molecular Genetics
- Phone: 434-243-6521
- Email: email@example.com
- Website: http://www.healthsystem.virginia.edu/internet/cellsignaling/bpaschal.cfm
Nuclear Transport, Signaling, and Cancer
My laboratory studies how nuclear transport and signal transduction control the compartmentalization and activity of transcription factors, particularly in the context of prostate cancer. A major focus of these studies is the androgen receptor (AR), a steroid hormone receptor that is critical for prostate cell growth. Translocation of AR through the nuclear pore complex (NPC) relies on features common to most nuclear transport pathways: (i) the use of nuclear import or export signals; (ii) the recognition of these signals by receptors that mediate translocation through the NPC; and (iii) RanGTPase-dependent assembly and disassembly of transport complexes.
The signals that specify nuclear import and export of AR, the receptors that mediate AR translocation, and the role of the RanGTPase in AR transport are all under investigation in my laboratory. Nuclear export would be expected to provide an effective mechanism for terminating the transcriptional response to androgen, however, we have recently found that AR translocation to the cytoplasm is important for its activity in the nucleus. This apparent paradox may reflect an undefined step in AR maturation, or crosstalk between AR and signal transduction pathways in the cytoplasm. AR is the target of multiple kinases, and we have generated phosphosite antibodies to study the pathways and functions of phospho-regulation. In the course of these studies we discovered a novel mechanism for loading protein phosphatase 2A (PP2A) onto AR. The loading mechanism requires small t antigen, a product encoded by SV40 that binds and alters the structure of a PP2A subunit. Current experiments are aimed at defining the structural basis of the PP2A loading reaction, as well as determining the cellular factors that mediate PP2A loading onto AR in untransformed cells.
While biochemical analysis is the cornerstone of our nuclear transport and signal transduction studies, we also employ cell biological approaches including microinjection, fluorescence microscopy and real-time imaging in live cells, and animal models of tumorigenesis. Our studies benefit from ongoing collaborations with groups that specialize in mass spectrometry, pathology, and prostate cancer.
- Datta S, Snow C, Paschal B. A pathway linking oxidative stress and the Ran GTPase system in progeria. Molecular biology of the cell. 2014;25(8): 1202-15. PMID: 24523287 | PMCID: PMC3982987
- Bjerke G, Yang C, Frierson H, Paschal B, Wotton D. Activation of Akt signaling in prostate induces a TGFβ-mediated restraint on cancer progression and metastasis. Oncogene. 2013. PMID: 23995785 | PMCID: PMC3939071
- Ni L, Llewellyn R, Kesler C, Kelley J, Spencer A, Snow C, Shank L, Paschal B. Androgen induces a switch from cytoplasmic retention to nuclear import of the androgen receptor. Molecular and cellular biology. 2013;33(24): 4766-78. PMID: 24100013 | PMCID: PMC3889559
- Paciorkowski A, Weisenberg J, Kelley J, Spencer A, Tuttle E, Ghoneim D, Thio L, Christian S, Dobyns W, Paschal B. Autosomal recessive mutations in nuclear transport factor KPNA7 are associated with infantile spasms and cerebellar malformation. European journal of human genetics : EJHG. 2013;22(5): 587-93. PMID: 24045845 | PMCID: PMC3992559
- Snow C, Dar A, Dutta A, Kehlenbach R, Paschal B. Defective nuclear import of Tpr in Progeria reflects the Ran sensitivity of large cargo transport. The Journal of cell biology. 2013;201(4): 541-57. PMID: 23649804 | PMCID: PMC3653351
- Sun D, Layer R, Mueller A, Cichewicz M, Negishi M, Paschal B, Dutta A. Regulation of several androgen-induced genes through the repression of the miR-99a/let-7c/miR-125b-2 miRNA cluster in prostate cancer cells. Oncogene. 2013. PMID: 23503464 | PMCID: PMC3915043
- Kelley J, Datta S, Snow C, Chatterjee M, Ni L, Spencer A, Yang C, Cubeñas-Potts C, Matunis M, Paschal B. The defective nuclear lamina in Hutchinson-gilford progeria syndrome disrupts the nucleocytoplasmic Ran gradient and inhibits nuclear localization of Ubc9. Molecular and cellular biology. 2011;31(16): 3378-95. PMID: 21670151 | PMCID: PMC3147792
- Kelley J, Talley A, Spencer A, Gioeli D, Paschal B. Karyopherin alpha7 (KPNA7), a divergent member of the importin alpha family of nuclear import receptors. BMC cell biology. 2010;11 63. PMID: 20701745 | PMCID: PMC2929220
- Ni L, Yang C, Gioeli D, Frierson H, Toft D, Paschal B. FKBP51 promotes assembly of the Hsp90 chaperone complex and regulates androgen receptor signaling in prostate cancer cells. Molecular and cellular biology. 2010;30(5): 1243-53. PMID: 20048054 | PMCID: PMC2820886
- Galgano M, Conaway M, Spencer A, Paschal B, Frierson H. PRK1 distribution in normal tissues and carcinomas: overexpression and activation in ovarian serous carcinoma. Human pathology. 2009;40(10): 1434-40. PMID: 19427017 | PMCID: PMC2744839
- Kelley J, Paschal B. Hyperosmotic stress signaling to the nucleus disrupts the Ran gradient and the production of RanGTP. Molecular biology of the cell. 2007;18(11): 4365-76. PMID: 17761537 | PMCID: PMC2043571
- Yang C, Xin H, Kelley J, Spencer A, Brautigan D, Paschal B. Ligand binding to the androgen receptor induces conformational changes that regulate phosphatase interactions. Molecular and cellular biology. 2007;27(9): 3390-404. PMID: 17325038 | PMCID: PMC1899975