Faculty: Randal S. Tibbetts
| Dept: | Associate Professor, Human Oncology |
|---|---|
| Contact: | 3036 WIMR 608-262-0027 rstibbetts@wisc.edu |
| Training Areas: | Molecular & Cellular Pharmacology Cellular & Molecular Biology |
Research Interests
Our group pursues several areas of investigation broadly pertaining to signal transduction in cancer and neurodegenerative disease. One project involves understanding cellular responses to DNA damage in the context of ataxia-telangiectasia, a syndrome of cancer susceptibility and cerebellar neurodegeneration caused by mutations in the ATM gene. ATM is a tumor suppressor that fulfills a pervasive regulatory role in the DNA damage response through phosphorylation of DNA repair-, cell cycle-, and apoptosis-associated protein; however, ATM is also involved in many other aspects of cellular regulation. Work from our group several years ago demonstrated that ATM phosphorylates the cyclic AMP response element binding protein (CREB), a highly conserved transcriptional regulator belonging to the larger family of bZIP transcription factors. CREB and the related protein ATF1 have been intensively studied for their roles in glucose homeostasis/obesity and long-term potentiation of neuronal synaptic transmission in vivo. Our studies indicate an unappreciated role for these factors in the DNA damage response and we are currently using cell-based and whole-animal (mouse) approaches to define this hypothesized function.
The other focus group in our lab studies molecular mechanisms of neurodegeneration in the motor neuron disease ALS and specifically how mutations in structurally related RNA-binding proteins TDP-43 and FUS/TLS cause ALS. We are using cell-based and in vitro approaches to understand TDP-43 functions and collaborate with the Wassarman laboratory at UW-Madison to understand how TDP-43 induces motor neuron degeneration in Drosophila. The long-term goals of these studies are to define key disease pathways that can therapeutically targeted in ALS.
Current lab members:
Sang Hwa Kim, Ph.D. (postdoc)
John Hutchinson (graduate student)
Lihong Zhan (graduate student)
Past lab members:
Sujatha Kumar, Ph.D. (graduate student; 2001-2006)
Gerald Dodson, Ph.D. (graduate student; 2001-2006)
Naval Shanware, Ph.D. (graduate student; 2004-2009)
Yuling Shi, Ph.D. (postdoctoral fellow; 2002-2007)
Ryo Sakasai, Ph.D. (postdoctoral fellow; 2006-2009)
Tony Trinh (graduate student; 2006-2013)
Leah Williams (technician)
Keith Hanson (MSTP student; 2008-2011)
Recent Publications
- Zhan L, Hanson KA, Kim SH, Tare A, Tibbetts RS. Identification of genetic modifiers of TDP-43 neurotoxicity in Drosophila. PLoS One. 2013;8(2):e57214. doi: 10.1371/journal.pone.0057214. Epub 2013 Feb 27. PMID: 23468938
- Kim SH, Zhan L, Hanson KA, Tibbetts RS High-content RNAi screening identifies the Type1 inositol triphosphate receptor as a modifier of TDP-43 localization and neurotoxicity. Hum Mol Genet. 2012 Nov 15;21(22):4845-56. doi: 10.1093/hmg/dds321. Epub 2012 Aug 7. PMID: 22872699
- Hanson KA, Kim SH, Tibbetts RS. RNA-binding proteins in neurodegenerative disease: TDP-43 and beyond.Wiley Interdiscip Rev RNA. 2012 Mar-Apr;3(2):265-85. doi: 10.1002/wrna.111. Epub 2011 Oct 25. Review. PMID: 22028183
- Shanware NP, Hutchinson JA, Kim SH, Zhan L, Bowler MJ, Tibbetts RS (2011). Casein kinase 1-dependent phosphorylation of familial advanced sleep phase syndrome-associated residues controls PERIOD 2 stability. J Biol Chem. 2286(14):12766-74. PMID: 21324900
- Hanson KA, Kim SH, Tibbetts RS (2011). RNA-binding proteins in neurodegenerative disease: TDP-43 and beyond. Wiley Interdiscip Rev RNA. PMID: 22028183
- Sakasai, R., Teraoka, H., Takagi, M., and Tibbetts, R.S. (2010) Transcription-dependent activation of ataxia telangiectasia-mutated prevents DNA-dependent protein kinase-mediated cell death in response to topoisomerase I poison. J. Biol. Chem. 285, 15201-8 [PMID: 20304914]
- Hanson, K.A., Kim, S.H., Wassarman, D.A. and Tibbetts, R.S. (2010) Ubiquilin modifies toxicity of the 43 kilodalton TAR-DNA binding protein (TDP-43) in a Drosophila model of amyotrophic lateral sclerosis (ALS). J. Biol. Chem. 285, 11068-72 [PMID: 20154090].
- Sakasai, R. and Teraoka, H., and Tibbetts, R.S. (2009). Proteasome inhibition suppresses DNA-dependent protein kinase activation caused by camptothecin. DNA Repair 9, 76-82 [PMCID: PMC2818427]
- Shanware, N.P., Williams, L.M., Bowler, M.B. and Tibbetts, R.S. (2009) Non-specific in vivo inhibition of CK1 by the pyridinyl imidazole p38 inhibitors SB203580 and SB202190. BMB Reports 42, 142-147. [PMID: 19336000]