Lau Laboratory

Jenny Cohen

Current Position:

Postdoctoral Fellow, Non-clinical Safety Dept., Hoffman-La Roche Inc, Nutley, NJ

Education:

  • Ph.D. Pharmacology and Toxicology, with minor in Cancer Biology University of Arizona 2004-2009
  • B.S. Biochemistry The University of Illinois Champaign-Urbana Champaign, IL 2004

Achievements:

  • 2nd place in the Renal Toxicology award, Mechanisms of Toxicology 2010
  • Caldwell Health Sciences Research Fellowship 2009
  • Honorable mention best student presentation at Annual SOT Carl C. Smith Graduate Student Award for Meritorious Research in Mechanisms of Toxicology 2009 
  •  3rd place in Student Abstract Competition  in the SOT Molecular Biology Specialty Section 2009
  • 2nd place Student Award for SOT Drug Discovery Toxicology Specialty Section 2009
  • NIEHS Toxicology and Toxicogenomics Training Program Predoctoral Trainee 2007-2009
  • 3rd place in Student Abstract Competition in the SOT Carcinogenesis Specialty Section 2008
  • SOT Women in Toxicology Specialty Section Student Achievement Award 2007
  • 1st place Graduate Student Best Poster Competition, MWSOT regional meeting 2007
  • Yuma Friends of Arizona Health Sciences Center Young Investigator Research Award 2005

Professional Experience:

  • University of Illinois, Urbana-Champaign Undergraduate Research Fellow 2003-2004

Research Project:

The tuberous sclerosis-2 (Tsc-2) gene functions as a renal tumor suppressor, and loss of heterozygosity (LOH) at the Tsc-2 locus has been noted in tumors of both tuberous sclerosis and sporadic patients. In both rats and mice, Tsc-2 is a major target for spontaneous renal cell carcinoma (RCC); but only in rats Tsc-2 is a target for chemically induced RCC as well. Treatment of Eker (Tsc-2EK/+) rats with 2,3,5-tris-(glutathion-S-yl) hydroquinone (TGHQ) results in loss of the wild-type allele of Tsc-2 in renal preneoplastic lesions and tumors. Furthermore, TGHQ transformation of primary renal epithelial cells derived from Tsc-2EK/+ rats (QTRRE cells) also results in LOH at the Tsc-2 allele, and cells are tuberin null. Additionally, subcutaneous injection of QTRRE cells in athymic nude mice promotes tumor formation.

My project focused on the mechanistic studies in these three RCC models have been carried out to determine how the tumor suppressor tuberin negatively regulates the Raf/MEK/ERK MAPK cascade. Analysis of kidney tumors formed in Tsc-2EK/+ rats following 8-months of TGHQ treatment reveals increases in B-Raf, Raf-1, pERK, cyclin D1, p27Kip1, 4EBP1, p-4EBP1(Thr70), p-4EBP1(Ser65), and p-4EBP1(Thr37/46) protein expression. These data establish the involvement of mTOR and MAPK signaling cascades in tuberin null tumors. Similar increases in 4EBP1 and p4EBP1 are observed in renal tumor xenografts derived from subcutaneous injection of QTRRE cells in nude mice. Concomitant with increases in expression of these proteins in TGHQ-induced renal tumors, similar changes are observed in QTRRE cells, which also exhibit high ERK, B-Raf and Raf-1 kinase activity; and increased expression of cyclin D1, p27, p-4EBP1. Manipulation of the Raf/MEK/ERK kinase cascade in QTRRE cells, with kinase inhibitors and siRNA, indicates that Raf-1/MEK/ERK participates in crosstalk with 4EBP1 to regulate translation of cyclin D1. 

Cyclin D1 and p27 protein levels are increased in the cytoplasm of all three RCC models. In normal human proximal tubule cells (HK-2), p27 and cyclin D1 are localized to the nucleus. Due to the instability of the cyclin D1-CDK4 complex, p27 interaction is necessary for complex assembly and stabilization. Therefore, the cyclin dependent kinase inhibitor p27 has been the focus of our studies, in an effort to determine the mechanism for cytoplasmic mislocalization and stabilization of cyclin D1. Manipulation of p27 protein levels in QTRRE cells with phosphodiesterase inhibitors, dibutyryl cAMP, and the proteosome inhibitor MG132, all result in a parallel increase in p27 and cyclin D1. Furthermore, p27 siRNA and sorafenib treatment both cause a decrease in p27 and cyclin D1. Further manipulation of cAMP, Rap1B, and B-Raf proteins, revealed that cAMP/PKA/Rap1B/B-Raf activation and B-Raf//ERK MAPK inhibition both modulate p27 expression and compartmental localization in tuberous sclerosis renal cancer. Phosphodiesterase inhibitors play a role in regulating the expression, degradation, and cytoplasmic localization of p27. Therefore, cytoplasmic p27-cyclin D1 mislocalization and stabilization may have an oncogenic role in the cytosol and play a crucial role in tumor formation.

Publications:

  • Cohen, J.D., Tham, K.Y., Mastrandrea, N.M., Gallegos, A.C., Monks, T.J., Lau, S.S. cAMP–Dependent Pathway(s) Directs the Rap-GTP/B-Raf MAPK Mediated Cytosolic Mislocalization of p27kip-cyclin D1 in Renal Cancer. Toxicological Sciences, in press 2011.

Abstracts:

  • cAMP-dependent pathway(s) increase p27kip-cyclin D1 through the Rap-GTP/B-Raf MAPK signaling pathway in Renal Cancer. Mastrandrea, N.J., Tham, K.Y., Cohen, J.D., Monks, T.J., and Lau, S.S. Toxicologist, 105, 823, 2011.

  • cAMP-Dependent pathway(s) directs the B-Raf MAPK-mediated cytosolic mislocalization of p27kip-cyclin D1 in Renal Cancer. Tham, K.Y., Cohen, J.D., Monks, T.J. and Lau, S.S. The FASEB Journal, 24:964.5, 2010.

  • cAMP-dependent pathway(s) directs the Rap-GTP/B-Raf MAPK-mediated cytosolic mislocalization of p27kip-cyclin D1 in renal cancer. Cohen, J.D., Tham, K.Y., Monks, T.J. and Lau, S.S. Toxicologist, 104, 518, 2010.

  • MALDI-MS-based drug and protein imaging to simultaneously determine drug disposition and protein modification in cells. Mastrandrea, N.J. Cohen, J.D., Kimzey, M., Monks, T.J. and Lau, S.S. Toxicologist, 104, 1667, 2010.

  • The tumor suppressor gene Tsc-2 modulates translation initiation of cyclin D1 through ERK crosstalk with 4EBP1. Cohen, J.D., Gard, J.M.C., Nagle, R.B., Monks, T.J., and Lau, S.S. Toxicologist, 103, 1412, 2009.

  • Constitutively active B-Raf does not regulate cyclin D1 in 2,3,5-Tris-(glutathion-S-yl) hydroquinone transformed, tuberous sclerosis-2 null cells. Cohen, J.D., Labenski, M.T., Monks, T.J. and Lau, S.S. Toxicologist, 102, 1412, 2008.

  • Detection of high MW proteins in MALDI-tissue imaging. BD Leinweber, JD Cohen, T.J. Monks, S.S. Lau. Toxicologist, 96, 2123, 2007.

  • Constitutively active B-Raf complexes with 14-3-3 isoforms and Raf-1 in Tsc-2 null-cells. Cohen, J.D., Monks, T.J. Lau, S.S. Toxicologist, 96, 1576, 2007.

Past and present staff

Present Graduate Students

Ryan Canatsey | Owen Kinsky | Chris Kuhlman | Nick Mastrandrea | Jessica Sapiro | Kevin Xu


Present Postdoctoral Fellow
Tim Radabaugh

Research Associate

Alfred Gallegos

Clinical Faculty Mentee

Hussein Yassine

Current Undergraduate Students

Wesley Cai, Itzel Rojas, Audrey Shi, Kim Tham


Recent Past Staff
Martina Bowen | Jennifer Cohen | Ashley Fisher | Chris Hattan | Mike Kimzey | Matt Labenski | Jean Lord-Garcia

 

 

 

 

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