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Kirk Jensen

Kirk Jensen
School of Biological Sciences
Faculty of Sciences

Biography
My research focuses on post-transcriptional gene regulation, and in particular, understanding the roles of RNA-binding proteins (RBPs) in controlling key RNA processing steps, from splicing through to translation initiation.
A long-standing methodological aspect of my work (beginning as a PhD student in Boulder, CO), has been the use of short-wave UV irradiation to induce covalent crosslinks between RBPs and their cognate RNA targets. At the Rockefeller University in New York, I used my knowledge of photo-crosslinking to invent CLIP (crosslinking-immunoprecipitation), a method which uses UV irradiation to covalently link an RBP to its entire cohort of cellular RNA targets in living cells, and which permits the subsequent isolation and sequencing of these linked RNA fragments. CLIP has seen numerous improvements over the years, including an early advance pairing the methodology with high-throughput sequencing (HITS-CLIP), and present-day versions of the technique are considered the gold standard for determining the cellular RNA target repertoire of an RBP.
My current research at SAHMRI focuses on translation initiation. The canonical translation initiation pathway is orchestrated by the eIF4E1 protein, which concurrently binds the m7G cap at the 5' end of the mRNA and the scaffolding protein eIF4G. Together these interactions permit the deposition of the 43S pre-initiation complex at the 5' end of the mRNA; once the AUG has been found though scanning, translation itself begins.
A major goal is to better understand how translation initiation (and specifically eIF4E1) is modulated by the Ras-MAPK and mTOR/mTORC1 signalling pathways, as these pathways can directly modify eIF4E1 itself or its binding partners (phosphorylation of eIF4E1 by the MNK kinases, phosphorylation of the 4E-BPs by mTORC1), or modify other core translation initiation factors (phosphorylation of S6K by mTORC1, for example). A second goal is to understand the function of the alternative human cap-binding protein, eIF4E2. While several lines of investigation indicate that eIF4E2 acts as a translational repressor (by interfering with the initiation function of eIF4E), other evidence suggests eIF4E2 supports translation, but only under conditions of cellular stress.
To address both of these goals, we are developing novel CLIP-like methodology to identify the cellular cohorts of mRNAs bound in vivo by either eIF4E1 or eIF4E2 under a wide range of environmental conditions, including inhibition of MNK and/or mTORC1 signalling using highly selective small molecule kinase inhibitors. Bioinformatic analysis of this set of specific eIF4E1 ‘cap-omes’ will permit the identification of those mRNAs which are strongly regulated by MNK and mTOR signalling and may also give us significant insight into the mechanisms which underlie the changes in translation of individual mRNA species. Similarly, analysis of the eIF4E2 ‘cap-omes’ should allow us to state with certainty if eIF4E2 acts as a repressor or as an activator of (an alternative pathway) of translation initiation, and by evaluating the environments in which we observe either (or both) activities we should develop a good understanding of the cellular contexts where eIF4E2 function is most critical, and why.

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External Profiles

Kirk Jensen

Biography
My research focuses on post-transcriptional gene regulation, and in particular, understanding the roles of RNA-binding proteins (RBPs) in controlling key RNA processing steps, from splicing through to translation initiation.
A long-standing methodological aspect of my work (beginning as a PhD student in Boulder, CO), has been the use of short-wave UV irradiation to induce covalent crosslinks between RBPs and their cognate RNA targets. At the Rockefeller University in New York, I used my knowledge of photo-crosslinking to invent CLIP (crosslinking-immunoprecipitation), a method which uses UV irradiation to covalently link an RBP to its entire cohort of cellular RNA targets in living cells, and which permits the subsequent isolation and sequencing of these linked RNA fragments. CLIP has seen numerous improvements over the years, including an early advance pairing the methodology with high-throughput sequencing (HITS-CLIP), and present-day versions of the technique are considered the gold standard for determining the cellular RNA target repertoire of an RBP.
My current research at SAHMRI focuses on translation initiation. The canonical translation initiation pathway is orchestrated by the eIF4E1 protein, which concurrently binds the m7G cap at the 5' end of the mRNA and the scaffolding protein eIF4G. Together these interactions permit the deposition of the 43S pre-initiation complex at the 5' end of the mRNA; once the AUG has been found though scanning, translation itself begins.
A major goal is to better understand how translation initiation (and specifically eIF4E1) is modulated by the Ras-MAPK and mTOR/mTORC1 signalling pathways, as these pathways can directly modify eIF4E1 itself or its binding partners (phosphorylation of eIF4E1 by the MNK kinases, phosphorylation of the 4E-BPs by mTORC1), or modify other core translation initiation factors (phosphorylation of S6K by mTORC1, for example). A second goal is to understand the function of the alternative human cap-binding protein, eIF4E2. While several lines of investigation indicate that eIF4E2 acts as a translational repressor (by interfering with the initiation function of eIF4E), other evidence suggests eIF4E2 supports translation, but only under conditions of cellular stress.
To address both of these goals, we are developing novel CLIP-like methodology to identify the cellular cohorts of mRNAs bound in vivo by either eIF4E1 or eIF4E2 under a wide range of environmental conditions, including inhibition of MNK and/or mTORC1 signalling using highly selective small molecule kinase inhibitors. Bioinformatic analysis of this set of specific eIF4E1 ‘cap-omes’ will permit the identification of those mRNAs which are strongly regulated by MNK and mTOR signalling and may also give us significant insight into the mechanisms which underlie the changes in translation of individual mRNA species. Similarly, analysis of the eIF4E2 ‘cap-omes’ should allow us to state with certainty if eIF4E2 acts as a repressor or as an activator of (an alternative pathway) of translation initiation, and by evaluating the environments in which we observe either (or both) activities we should develop a good understanding of the cellular contexts where eIF4E2 function is most critical, and why.

Please see my Researcher Profiles at SAHMRI, ORCID, and Scopus

Appointments

Date Position Institution name
2016 Affiliate Associate Professor University of Adelaide
2016 Senior Research Fellow South Australian Health and Medical Research Institute
2004 - 2015 Senior Lecturer University of Adelaide
2001 - 2003 Research Assistant Professor Rockefeller University

Education

Date Institution name Country Title
1991 - 1995 University of Colorado Boulder United States PhD (Chemistry and Biochemistry)
1983 - 1997 Stanford University United States BS (Biological Sciences)

Postgraduate Training

Date Title Institution Country
1996 - 2001 Postdoctoral Fellow Rockefeller University United States
1996 - 1996 Postdoctoral Associate University of Colorado Boulder United States

Journals

Year Citation
2016 Bramham, C., Jensen, K., & Proud, C. (2016). Tuning specific translation in cancer metastasis and synaptic memory: control at the MNK-eIF4E axis. Trends in Biochemical Sciences, 41(10), 847-858.
DOI Scopus18 WoS15 Europe PMC14
2014 Bracken, C. P., Li, X., Wright, J. A., Lawrence, D., Pillman, K. A., Salmanidis, M., . . . Goodall, G. (2014). Genome-wide identification of miR-200 targets reveals a regulatory network controlling cell invasion. The EMBO Journal, 33(18), 1979-2134.
DOI Scopus71 WoS72 Europe PMC56
2012 Ince-Dunn, G., Okano, H. J., Jensen, K. B., Park, W. -Y., Zhong, R., Ule, J., . . . Darnell, R. B. (2012). Neuronal elav-like (Hu) proteins regulate RNA splicing and abundance to control glutamate levels and neuronal excitability. Neuron, 75(6), 1067-1080.
DOI Scopus86 WoS90 Europe PMC82
2011 Dredge, B., & Jensen, K. (2011). NeuN/Rbfox3 nuclear and cytoplasmic isoforms differentially regulate alternative splicing and nonsense-mediated decay of Rbfox2. PLoS One, 6(6), e21585-1-e21585-12.
DOI Scopus56 WoS56 Europe PMC48
2011 Wiszniak, S., Dredge, B., & Jensen, K. (2011). HuB (elavl2) mRNA is restricted to the germ cells by post-transcriptional mechanisms including stabilisation of the message by DAZL. PLoS One, 6(6), e20773-1-e20773-9.
DOI Scopus16 WoS15 Europe PMC13
2005 Ule, J., Jensen, K., Mele, A., & Darnell, R. (2005). CLIP: A method for identifying protein-RNA interaction sites in living cells. Methods-A Companion to Methods in Enzymology, 37(4), 376-386.
DOI Scopus359 WoS343 Europe PMC283
2003 Ule, J., Jensen, K., Ruggiu, M., Mele, A., Ule, A., & Darnell, R. (2003). CLIP Identifies Nova-Regulated RNA Networks in the Brain. Science, 302(5648), 1212-1215.
DOI Scopus605 WoS582 Europe PMC470
2001 Nicolas, M., Noe, V., Jensen, K., & Ciudad, C. (2001). Cloning and characterization of the 5'-flanking region of the human transcription factor Sp1 gene. Journal of Biological Chemistry, 276(25), 22126-22132.
DOI Scopus73 WoS73 Europe PMC47
2001 Darnell, J., Jensen, K., Jin, P., Brown, V., Warren, S., & Darnell, R. (2001). Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function. Cell, 107(4), 489-499.
DOI Scopus661 WoS642 Europe PMC499
2001 Musunuru, K., Lewis, H. A., Jensen, K. B., Edo, C., Chen, H., Darnell, R. B., & Burley, S. K. (2001). Structure/function studies of the K-homology (KH) RNA-binding motif. COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY, 66, 110.
2000 Jensen, K., Musunuru, K., Lewis, H., Burley, S., & Darnell, R. (2000). The tetranucleotide UCAY directs the specific recognition of RNA by the Nova K-homology 3 domain. Proceedings of the National Academy of Sciences of the United States of America, 97(11), 5740-5745.
DOI Scopus100 WoS103 Europe PMC79
2000 Jensen, K., Dredge, B., Stefani, G., Zhong, R., Buckanovich, R., Okano, H., . . . Darnell, R. (2000). Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability. Neuron, 25(2), 359-371.
DOI Scopus272 WoS262 Europe PMC210
2000 Lewis, H., Musunuru, K., Jensen, K., Edo, C., Chen, H., Darnell, R., & Burley, S. (2000). Sequence-specific RNA binding by a Nova KH domain: Implications for paraneoplastic disease and the fragile X syndrome. Cell, 100(3), 323-332.
DOI Scopus239 WoS238 Europe PMC192
1998 Morris, K., Jensen, K., Julin, C., Weil, M., & Gold, L. (1998). High affinity ligands from in vitro selection: Complex targets. Proceedings of the National Academy of Sciences of the United States of America, 95(6), 2902-2907.
DOI Scopus232 WoS224 Europe PMC134
1995 Jensen, K., Atkinson, B., Willis, M., Koch, T., & Gold, L. (1995). Using in vitro selection to direct the covalent attachment of human immunodeficiency virus type 1 Rev protein to high-affinity RNA ligands. Proceedings of the National Academy of Sciences of the United States of America, 92(26), 12220-12224.
DOI Scopus111 WoS102 Europe PMC46
1994 Jensen, K., Green, L., MacDougal-Waugh, S., & Tuerk, C. (1994). Characterization of an in vitro-selected RNA ligand to the HIV-1 rev protein. Journal of Molecular Biology, 235(1), 237-247.
DOI Scopus46 WoS41 Europe PMC26

Book Chapters

Conference Papers

Year Citation
2005 Dredge, B., Webb, J., & Jensen, K. (2005). The role of the neuronal Hu RNA-binding proteins in the developing nervous system.. In 4th European Zebrafish Genetics and Development Meeting. Dresden, Germany.
2005 Webb, J., Dredge, B., & Jensen, K. (2005). Molecular and developmental roles of the neuron-specific RNA-binding protein Huc in the zebrafish nervous system. In MECHANISMS OF DEVELOPMENT Vol. 122 (pp. S169-S170). ELSEVIER SCIENCE BV PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS.
2005 Sibbons, J., McCarthy, P., Dredge, B., & Jensen, K. (2005). The neuron-specific HuD RNA-binding protein is important for proper development of the zebrafish sensory nervous system. In MECHANISMS OF DEVELOPMENT Vol. 122 (pp. S169). ELSEVIER SCIENCE BV.
2004 Dredge, B. K., Darnell, R. B., & Jensen, K. B. (2004). Molecular dissection of a neurological disorder: the role of Nova and Hu in RNA processing.. Australian Society for Medical Research.
1995 Koch, T. H., Jensen, K. B., Atkinson, B. L., & Willis, M. C. (1995). Photoselex. A Strategy for Identifying a Nucleic Acid which Will Bind and Photocrosslink to a Molecular Target. In PHOTOCHEMISTRY AND PHOTOBIOLOGY Vol. 61 (pp. SAM-B3). PERGAMON PRESS.

Conference Items

Patents

Year Citation
2011 Darnell, R., Jensen, K., & Ule, J. (2011). US20110076676 A1, Method of purifying RNA binding protein-RNA complexes. US.
2005 Darnell, R., Jensen, K., & Ule, J. (2005). US20050227251 A1, Method of purifying RNA binding protein-RNA complexes. US.
2002 Gold, L., Willis, M., Koch, T., Ringquist, S., Jensen, K., & Atkinson, B. (2002). 6482594, Systematic evolution of ligands by exponential enrichment: photoselection of nucleic acid ligands. US.
2001 Gold, L., Willis, M., Koch, T., Ringquist, S., Jensen, K., & Atkinson, B. (2001). US6291184, Systematic evolution of ligands by exponential enrichment: photoselection of nucleic acid ligands and solution selex. US.
2001 Gold, L., Eaton, B., Smith, D., Jensen, K., & Wecker, M. (2001). 6300074, Systematic evolution of ligands by exponential enrichment: Chemi-SELEX. US.
2000 Jensen, K. B., Chen, H., Morris, K. N., Stephens, A., & Gold, L. (2000). US6114120, Systematic evolution of ligands by exponential enrichment: tissue selex. US.
1999 Gold, L., Eaton, B., Smith, D., Wecker, M., & Jensen, K. (1999). US5998142, Systematic evolution of ligands by exponential enrichment: Chemi-SELEX. US.
1999 Jensen, K., Chen, H., Morris, K. N., Stephens, A., & Gold, L. (1999). US5864026, Systematic evolution of ligands by exponential enrichment: tissue selex. US.
1999 Gold, L., Eaton, B., Smith, D., Wecker, M., & Jensen, K. (1999). US5962219, Systematic evolution of ligands by exponential enrichment: Chemi-SELEX. US.
1999 Gold, L., Willis, M., Koch, T., Ringquist, S., Jensen, K., & Atkinson, B. (1999). US6001577, Systematic evolution of ligands by exponential enrichment: photoselection of nucleic acid ligands and solution selex. US.
1998 Gold, L., Willis, M., Koch, T., Ringquist, S., Jensen, K., & Atkinson, B. (1998). US5763177, Systematic evolution of ligands by exponential enrichment: photoselection of nucleic acid ligands. US.
1998 Gold, L., Eaton, B., Smith, D., Wecker, M., & Jensen, K. (1998). US5763595, Systematic evolution of ligands by exponential enrichment: Chemi-SELEX. US.
1998 Gold, L., Eaton, B., Smith, D., Wecker, M., & Jensen, K. (1998). US5705337, Systematic evolution of ligands by exponential enrichment: Chemi-SELEX. US.
1998 Jensen, K. B., Chen, H., Morris, K. N., Stephens, A., & Gold, L. (1998). US5712375, Systematic evolution of ligands by exponential enrichment: tissue selex. US.
1998 Jensen, K. B., Chen, H., Morris, K. N., Stephens, A., & Gold, L. (1998). US5763566, Systematic evolution of ligands by exponential enrichment: tissue SELEX. US.
1998 Chen, H., Gold, L., Jensen, K. B., Morris, K. N., & Stephens, A. (1998). US5789157 A, Systematic evolution of ligands by exponential enrichment: tissue selex. US.

Theses

Year Citation
1995 Jensen, K. B. (1995). Enhancements of the SELEX methodology: biased randomization in vitro selection, in vitro selection of crosslinking nucleic acid ligands, and the application of in vitro selection to complex targets. (PhD Thesis).

Past Higher Degree by Research Supervision (University of Adelaide)

Date Role Research Topic Program Degree Type Student Load Student Name
2015 - 2017 Co-Supervisor Novel Roles of the MAP Kinase - interacting Kinases Doctor of Philosophy Doctorate Full Time Miss Shuye Tian
2013 - 2014 Principal Supervisor PSC1: A PROTEIN WITH MULTIPLE ROLES IN RNA METABOLISM Doctor of Philosophy Doctorate Full Time Ms Philippa Davey
2011 - 2013 Principal Supervisor Identification of Protein-RNA and Protein-Protein Interactions by the Neuronal HuC Protein of Mus musculus Master of Philosophy Master Full Time Mr Bradley Simpson
2007 - 2011 Principal Supervisor Investigating Mechanisms of Post-transcriptional Gene Regulation in the Germ Cells of Zebrafish Doctor of Philosophy Doctorate Full Time Miss Sophie Wiszniak
2007 - 2011 Co-Supervisor Sox3 Dosage Regulation is Important for Roof Plate Specification during Central Nervous System Development Doctor of Philosophy Doctorate Full Time Mrs Kristie Rogers
2005 - 2011 Principal Supervisor Investigation into The Molecular Function of The Neuronal Hu RNA Binding Protein, HuCsv1 Doctor of Philosophy Doctorate Full Time Mr Peter McCarthy
2002 - 2005 Co-Supervisor Investigating the Role of EphA/ ephrin-A Signalling During Trigeminal Ganglion Axon Guidance Doctor of Philosophy Doctorate Full Time Ms Chathurani Jayasena
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