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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 vivoby 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.

Education/Academic qualification

PhD, University of Colorado Boulder

1 Sep 199131 Dec 1995

Bachelor's Degree, Stanford University

1 Sep 198330 Jun 1987

External positions

Affiliate Associate Professor, University of Adelaide

1 Feb 20161 Feb 2020

Keywords

  • QD Chemistry
  • mRNA
  • RNA-binding protein
  • post-transcriptional gene regulation
  • translation initiation
  • ribosome
  • HITS-CLIP
  • CLIPseq
  • RNAseq
  • translational control
  • 5' UTR
  • 3' UTR

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Research Output 1994 2019

  • 3187 Citations
  • 16 h-Index
  • 15 Article
  • 8 Patent
  • 1 Chapter
  • 1 Review article
2 Citations (Scopus)

The MAP kinase-interacting kinases (MNKs) as targets in oncology

Xie, J., Merrett, J. E., Jensen, K. B. & Proud, C. G., 4 Mar 2019, In : Expert Opinion on Therapeutic Targets. 23, 3, p. 187-199 13 p.

Research output: Contribution to journalArticle

Method Of Purifying RNA Binding Protein-RNA Complexes

Jensen, K., 20 Sep 2016, IPC No. US 9447454 B2, United States Patent & Trademark Office, Patent No. US 9447454 B2

Research output: Patent

Open Access
File
29 Citations (Scopus)

Tuning Specific Translation in Cancer Metastasis and Synaptic Memory: Control at the MNK–eIF4E Axis

Bramham, C. R., Jensen, K. B. & Proud, C. G., 1 Oct 2016, In : Trends in Biochemical Sciences. 41, 10, p. 847-858 12 p.

Research output: Contribution to journalReview article

76 Citations (Scopus)

Genome-wide identification of miR-200 targets reveals a regulatory network controlling cell invasion

Bracken, C. P., Li, X., Wright, J. A., Lawrence, D. M., Pillman, K. A., Salmanidis, M., Anderson, M. A., Dredge, B. K., Gregory, P. A., Tsykin, A., Neilsen, C., Thomson, D. W., Bert, A. G., Leerberg, J. M., Yap, A. S., Jensen, K. B., Khew-Goodall, Y. & Goodall, G. J., 1 Jan 2014, In : EMBO Journal. 33, 18, p. 2040-2056 17 p.

Research output: Contribution to journalArticle

96 Citations (Scopus)

Neuronal Elav-like (Hu) Proteins Regulate RNA Splicing and Abundance to Control Glutamate Levels and Neuronal Excitability

Ince-Dunn, G., Okano, H. J., Jensen, K., Park, W. Y., Zhong, R., Ule, J., Mele, A., Fak, J. J., Yang, C. W., Zhang, C., Yoo, J., Herre, M., Okano, H., Noebels, J. L. & Darnell, R. B., 20 Sep 2012, In : Neuron. 75, 6, p. 1067-1080 14 p.

Research output: Contribution to journalArticle