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Leslie A. Krushel, Ph.D.

Present Title & Affiliation

Primary Appointment

Associate Professor, Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX

Research Interests

Research Interests:

  • RNA
  • Translation
  • Protein synthesis
  • Alzheimer's Disease
  • Cancer
  • Aurora kinases
  • Learning and memory
  • Amyloid precursor protein

We are interested in RNA biology.  Our goals are to understand the basic and fundamental mechanisms of protein synthesis and determine how these mechanisms contribute to both normal and disease states, in particular, Alzheimer's Disease and cancer.  The major mechanism to regulate protein synthesis is at the step of initiation.  Initiating translation of a messenger RNA requires recruiting the ribosome to the mRNA and positioning it at the initiator codon (AUG).  The major mechanism for these processes is called the cap/scanning model whereby the cap-binding protein binds the very 5' end of the mRNA (the m7G cap structure) and recruits the translational machinery including the 40S ribosome.  The ribosome, in turn, migrates or scans along the 5' leader (or untranslated region) until it encounters an AUG in a proper context.  An alternative and less well understood mechanism is the recruitment of the ribosome by the 5' leader.  These regions downstream of the cap structure are called internal ribosomal entry sites (IRESes).  IRESes have been best studied in a subset of viruses including poliovirus and Hepatitis C.  To date, only a small percentage of eukaryotic mRNAs have been shown to contain an IRES and the mechanism and function of these eukaryotic IRESes is not well understood.  It is proposed that conditions that inhibit or down-regulate cap-dependent translation maintain or up-regulate IRES-dependent translation.  These same conditions contribute to Alzheimer's Disease and cancer.  Indeed, our lab has identifed IRESes in mRNAs that code for proteins that are essential for the etiology of Alzheimer's Disease (Amyloid Precursor protein and Tau protein) as well as contribute to carcinogenesis (Aurora A Kinase).  We are presently identifying cis IRES elements (RNA sequences and RNA structure required for IRES activity), as well as trans IRES elements (proteins that bind the IRES and recruit the translational machinery).  In addition, we are examining the regulation (or mis-regulation) of the above IRESes in part by identifying intracellular signaling pathways that potentially lead to the post-translational modification of specific RNA-binding proteins.  Finally, we are examining the in vivo relevance of IRES-dependent translation through the study of neuronal protein synthesis in culture as well as the creation of transgenic animals.

Projects/Techniques: Essentially we cover a wide array of molecular, cellular, and biochemical techniques to identify RNA sequences and RNA structure, novel proteins, levels of protein synthesis, post-translational modification of proteins, regulation of protein synthesis in-vitro, ex-vivo and in-vivo, intracellular pathways that regulate IRES activity, etc.  Students will be trained in the techniques appropriate to the projects in which they are interested.

Office Address

The University of Texas MD Anderson Cancer Center
6767 Bertner Street
Department of Biochemistry & Molecular Biology
Unit Number: 1000
Houston, TX 77030
Room Number: S9.8136C
Phone: (713) 834-6310 (office); 834-6303 (Lab)
Fax: (713) 834-6273
Email: lkrushel@mdanderson.org

Education & Training

Degree-Granting Education

1990 University of Toronto, Toronto, Ontario, Canada, PHD, Neuroscience
1984 University of Lethbridge, Lethbridge, Canada, BS, Psychology

Postgraduate Training

1998-2000 Associate Fellow, The Neurosciences Institute, La Jolla, CA
1994-1997 Junior Fellow, The Neurosciences Institute, La Jolla, CA
1992-1994 Senior Research Associate, The Scripps Research Institute, La Jolla, CA, Gerald Edelman
1990-1992 Postdoctoral Research, Rockefeller University, New York, NY, Gerald Edelman

Experience/Service

Academic Appointments

Associate Professor, University of Colorado Denver School of Medicine, Denver, CO, 2008-2010
Assistant Professor, University of Colorado Denver School of Medicine, Denver, CO, 2000-2008

Institutional Committee Activities

Member, Member of the UC Denver Medical School Honor Code Committee, UC Denver, 2009-2010
member, Dept. of Biochemistry and Molecular Genetics Education Committee, 2008-2010
Member, Mental Retardation and Developmental Disabilities Research Center, UC Denver, 2008-2010
Member, Dept. of Biochemistry and Molecular Genetics Admissions Committee, UC Denver, 2007-2010
Member, Dept. of Pharmacology Opening Committee, UC Denver, 2004
Member, Dept. of Pharmacology Graduate Admissions Committee, UC Denver, 2003-2005
Member, UCHSC Biosafety Committee, 2003
Chair, Molecular Biology Retreat, UC Denver, 2003
Member, Dept. of Pharmacology Library Committee, UC Denver, 2003
Chair, Neuroscience Program Admissions Committee, UC Denver, 2002-2004
Member, Neuroscience Program Steering Committee, UC Denver, 2002-2004
Co-Chair, Molecular Biology Retreat, UC Denver, 2002
Member, BSP Graduate Admissions Committee, UC Denver, 2002
Member, Dept. of Pediatrics Faculty Search Committee, UC Denver, 2002
Member, Neuroscience Program Graduate Admissions Committee, UC Denver, 2001-present
Member, Neuroscience Program Faculty Search Committee, UC Denver, 2001

Honors and Awards

2000-2001 Individual Investigator Award, UCHSC/HHMI
1990-1993 Medical Research Council Postdoctoral Fellowship
1989-1990 Ontario Graduate Fellowship
1989 Mitchell Scholarship
1984-1989 Medical Research Council Studentship
1982 George Ellis Scholarship
1981-1982 Province of Alberta Undergraduate Scholarship
1981-1982 Undergraduate Summer Research Award, National Science & Engineering Research Council
1980 University of Lethbridge Entrance Scholarship, University of Lethbridge

Selected Publications

Peer-Reviewed Original Research Articles

1. Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N, Krushel L, Aukerman SL, Heise C, MacBeth KJ. A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One 5(2):e9001, 2010. PMCID: PMC2814859.
2. Veo BL, Krushel LA. Translation initiation of the human tau mRNA through an internal ribosomal entry site. J Alzheimers Dis 16(2):271-5, 2/2009. PMID: 19221416.
3. Beaudoin ME, Poirel VJ, Krushel LA. Regulating amyloid precursor protein synthesis through an internal ribosomal entry site. Nucleic Acids Res 36(21):6835-47, 12/2008. e-Pub 10/25/2008. PMCID: PMC2588504.
4. Dobson T, Kube E, Timmerman S, Krushel LA. Identifying intrinsic and extrinsic determinants that regulate internal initiation of translation mediated by the FMR1 5' leader. BMC Mol Biol 9:89, 2008. PMCID: PMC2576346.
5. Timmerman SL, Pfingsten JS, Kieft JS, Krushel LA. The 5' leader of the mRNA encoding the mouse neurotrophin receptor TrkB contains two internal ribosomal entry sites that are differentially regulated. PLoS One 3(9):e3242, 2008. PMCID: PMC2531235.
6. Li PW, Li J, Timmerman SL, Krushel LA, Martin SL. The dicistronic RNA from the mouse LINE-1 retrotransposon contains an internal ribosome entry site upstream of each ORF: implications for retrotransposition. Nucleic Acids Res 34(3):853-864, 2006. PMCID: PMC1361618.
7. Dobson T, Minic A, Nielsen K, Amiott E, Krushel L. Internal initiation of translation of the TrkB mRNA is mediated by multiple regions within the 5' leader. Nucleic Acids Res 33(9):2929-41, 2005. PMCID: PMC1133793.
8. Salbaum JM, Cirelli C, Walcott E, Krushel LA, Edelman GM, Tononi G. Chlorotoxin-mediated disinhibition of noradrenergic locus coeruleus neurons using a conditional. Brain Res 1016(1):20-32, 7/30/2004. PMID: 15234248.
9. Pinkstaff JK, Chappell SA, Mauro VP, Edelman GM, Krushel LA. Internal initiation of translation of five dendritically-localized neuronal mRNAs. Proc Natl Acad Sci U S A 98(5):2770-2775, 2/27/2001. e-Pub 2/20/2001. PMCID: PMC30214.
10. Little EB, Crossin KL, Krushel LA, Edelman GM, Cunningham BA. A short segment within the cytoplasmic domain of the neural cell adhesion molecule (N-CAM) is essential for N-CAM-induced NF-kappa B activity in astrocytes. Proc Natl Acad Sci U S A 98(5):2238-43, 2/2001. e-Pub 2/2001. PMCID: PMC30122.
11. Choi J, Krushel LA, Crossin KL. NF-kappaB activation by N-CAM and cytokines in astrocytes is regulated by multiple protein kinases and redox modulation. Glia 33(1):45-56, 1/2001. PMID: 11169791.
12. Crossin KL, Krushel LA. Cellular signaling by neural cell adhesion molecules of the immunoglobulin superfamily. Dev Dyn 218(2):260-279, 6/2000. PMID: 10842356.
13. Vanderklish PW, Krushel LA, Holst BH, Gally JA, Crossin KL, Edelman GM. Marking synaptic activity in dendritic spines with a calpain substrate exhibiting fluorescence resonance energy transfer. Proc Natl Acad Sci U S A 97(5):2253-2258, 2/29/2000. PMCID: PMC15787.
14. Krushel LA, Cunningham BA, Edelman GM, Crossin KL. NF-kappaB activity is induced by neural cell adhesion molecule binding to neurons and astrocytes. J Biol Chem 274(4):2432-9, 1/1999. PMID: 9891013.
15. Phillips GR, Krushel LA, Crossin KL. Domains of tenascin involved in glioma migration. J Cell Sci 111:1095-1104, 4/1998. PMID: 9512505.
16. Holst BD, Vanderklish PW, Krushel LA, Zhou W, Langdon RB, McWhirter JR, Edelman GM, Crossin KL. Allosteric modulation of AMPA-type glutamate receptors increases activity of the promoter for the neural cell adhesion molecule, N-CAM. Proc Natl Acad Sci U S A 95(5):2597-602, 3/1998. PMCID: PMC19427.
17. Krushel LA, Tai MH, Cunningham BA, Edelman GM, Crossin KL. Neural cell adhesion molecule (N-CAM) domains and intracellular signaling pathways involved in the inhibition of astrocyte proliferation. Proc Natl Acad Sci U S A 95(5):2592-6, 3/1998. PMCID: PMC19425.
18. Phillips GR, Krushel LA, Crossin KL. Developmental expression of two rat sialyltransferases that modify the neural cell adhesion molecule, N-CAM. Brain Res Dev Brain Res 102(2):143-155., 9/20/1997. PMID: 9352097.
19. Crossin KL, Tai MH, Krushel LA, Mauro VP, Edelman GM. Glucocorticoid receptor pathways are involved in the inhibition of astrocyte proliferation. Proc Natl Acad Sci U S A 94(6):2687-2692, 3/18/1997. PMCID: PMC20150.
20. Wang Y, Krushel LA, Edelman GM. Targeted DNA recombination in vivo using an adenovirus carrying the Cre recombinase gene. Proc Natl Acad Sci U S A 93(9):3932-3936., 4/30/1996. PMCID: PMC39462.
21. Wang Y, Jones FS, Krushel LA, Edelman GM. Embryonic expression patterns of the neural cell adhesion molecule gene are regulated by homeodomain binding sites. Proc Natl Acad Sci U S A 93(5):1892-1896, 3/5/1996. PMCID: PMC39878.
22. Hoffarth RM, Johnston JG, Krushel LA, van der Kooy D. The mouse mutation reeler causes increased adhesion within a subpopulation of early post-mitotic cortical neurons. J Neurosci 15(7 Pt 1):4838-4850., 7/1995. PMID: 7623115.
23. Krushel LA, Fishell G, van der Kooy D. Pattern formation in the mammalian forebrain: Striatal patch and matrix neurons intermix prior to compartment formation. Eur J Neurosci 7(6):1210-1219, 6/1/1995. PMID: 7582094.
24. Krushel LA, Sporns O, Cunningham BA, Crossin KL, Edelman GM. Neural cell adhesion molecule (N-CAM) inhibits astrocyte proliferation after injury to different regions of the adult rat brain. Proc Natl Acad Sci U S A 92(10):4323-7, 5/1995. PMCID: PMC41936.
25. Hazan R, Krushel L, Crossin KL. EGF receptor-mediated signals are differentially modulated by concanavalin A. J Cell Physiol 162(1):74-85., 1/1995. PMID: 7814452.
26. Krushel LA, Prieto AL, Edelman GM, Crossin KL. Differential effects of cytotactin/tenascin fusion proteins on intracellular pH and cell morphology. J Cell Physiol 161(3):508-518, 12/1994. PMID: 7525616.
27. Mauro VP, Wood IC, Krushel L, Crossin KL, Edelman GM. Cell adhesion alters gene transcription in chicken embryo brain cells and mouse embryonal carcinoma cells. Proc Natl Acad Sci U S A 91(7):2868-72, 3/1994. PMCID: PMC43472.
28. Krushel LA, van der Kooy D. Pattern formation in the developing mammalian forebrain: selective adhesion of early but not late postmitotic cortical and striatal neurons within forebrain reaggregate cultures. Dev Biol 158(1):145-62, 7/1993. PMID: 8330669.
29. Krushel LA, Prieto AL, Cunningham BA, Edelman GM. Expression patterns of the cell adhesion molecule Nr-CAM during histogenesis of the chick nervous system. Neuroscience 53(3):797-812, 4/1993. PMID: 8487956.
30. Krushel LA, Johnston JG, Fishell G, Tibshirani R, van der Kooy D. Spatially localized neuronal cell lineages in the developing mammalian forebrain. Neuroscience 53(4):1035-47, 4/1993. PMID: 7685067.
31. Mauro VP, Krushel LA, Cunningham BA, Edelman GM. Homophilic and heterophilic binding activities of Nr-CAM, a nervous system cell adhesion molecule. J Cell Biol 119(1):191-202, 10/1992. PMCID: PMC2289630.
32. Krushel LA, Connolly JA, van der Kooy D. Pattern formation in the mammalian forebrain: patch neurons from the rat striatum selectively reassociate in vitro. Brain Res Dev Brain Res 47(1):137-42, 5/1989. PMID: 2736761.
33. Krushel LA, van der Kooy D. Visceral cortex: integration of the mucosal senses with limbic information in the rat agranular insular cortex. J Comp Neurol 270(1):39-54, 62-3, 4/1988. PMID: 2453537.
34. Dobson T, Krushel LA. Enhanced IRES-dependent translation of the Aurora A mRNA contributes to elevated levels of Aurora A kinase in breast cancer cell lines. Submitted.
35. Beaudoin M, Maraia RJ, Krushel LA. La/SSB protein regulates IRES-dependent. Submitted.
36. Wie S, Krushel LA. The different 5' leaders in the thymidylate synthase mRNA exhibit diverse effects on translation. Mol Cancer Res. Submitted.

Book Chapters

1. Johnston, J. G., Fishell, G., Krushel, L. A., and van der Kooy, D. Development of striatal. In: Basal Ganglia III: Structure and Function. Ed(s) M.B. Carpenter and A. Plenum: New York, 9-17, 1991.
2. van der Kooy, D., Fishell, G., Krushel, L. A. and Johnston, J. G. The development of striatal compartments: From proliferation to patches. In: Basal Ganglia II: Structure and Function. Ed(s) M.B. Carpenter and A. Jayaraman (eds. Plenum: New York, 81-98, 1987.

Grant & Contract Support

Title: The role of 5-azacytidine on RNA processes in leukemia
Funding Source: Celgene
Role: Principal Investigator
Duration: 10/1/2008 - 12/30/2009
 
Title: Translational regulation in Alzheimerís Disease
Funding Source: NIH/NINDS
Role: Principal Investigator
Duration: 7/1/2007 - 6/30/2013
 
Title: Translation regulation in Alzheimerís Disease
Funding Source: NIA
Role: Principal Investigator
Duration: 10/1/2002 - 9/30/2003
 
Title: Mechanisms and regulation of translation in dendrites.
Funding Source: NIH/NINDS
Role: Principal Investigator
Duration: 12/1/2001 - 11/30/2006
 
Title: Integrative Neuroscience Initiative on Alcoholism
Funding Source: NIAAA
Role: Co-Principal Investigator
Principal Investigator: Zawada
Duration: 9/28/2001 - 9/27/2005
 
Title: Integrative Neuroscience Initiative on Alcoholism
Funding Source: NIAAA
Role: Principal Investigator
Duration: 9/28/2001 - 9/27/2003
 
Funding Source: University of Colorado
Role: Principal Investigator
Duration: 10/1/2000 - 9/30/2001

Last updated: 12/13/2013