Jack D. Keene

Last updated
Jack Donald Keene
Born
Jack Donald Keene

(1947-06-22)June 22, 1947
Jacksonville, Florida
Alma mater University of California, Riverside, University of Washington
Scientific career
Institutions Duke University

Jack D. Keene (born June 22, 1947, Jacksonville, Florida) is a James B. Duke Professor of Molecular Genetics and Microbiology at Duke University. [1]

Contents

Keene studies the regulation of RNA and the mechanisms of RNA-protein interactions. [2] [3] He identified RNA recognition motif (RRM) proteins, which are the largest family of RNA-binding proteins. He isolated the first human autoimmune antigen. He formalized the posttranscriptional operon and regulon (PTRO) model to describe global gene regulation, and proposed the RNA regulon hypothesis to better understand post-transcriptional regulation of mRNAs encoding proteins. [3] [4] Keene introduced the RIP (ribonucleoprotein immunoprecipitation) protocol for isolating specific mRNPs, which has become a tool for the mapping of mRNA targets of specific RBPs. [5]

Early life and education

Jack Donald Keene was born in Jacksonville, Florida on June 22, 1947. His father worked for the RAND Corporation. [6] [7] Keene attended Redlands High School in Redlands, California, graduating in 1965. [1]

Initially a student at University of California, Los Angeles (UCLA), he transferred to the University of California, Riverside, where he majored in biology, working with Carlton Bovell. [6] He received his A.B. degree in 1969. [7] Next, Keene studied with Helen Riaboff Whiteley at the University of Washington in Seattle, Washington, graduating in 1975 with a doctorate in microbiology and Immunology. [1] [6]

He did postdoctoral work in molecular virology with Robert A. Lazzarini in the Laboratory for Molecular Genetics at the National Institutes of Health in Bethesda, Maryland from 1974 to 1978. [3] [1] [6] [7]

Career

In 1979, Keene was recruited by Wolfgang Joklik to the Department of Microbiology and Immunology at Duke University Medical Center. At that time the department was ranked one of the top three in the United States by the National Research Council. [3] Keene was the chairman of the Department of Microbiology from 1992 to 2002, [3] and Director of Basic Sciences for the Duke Comprehensive Cancer Center from 1995 to 2003. [7] As of 1997 he became the James B. Duke Professor of Molecular Genetics and Microbiology at Duke University. [8] In 1999 Keene founded the Duke Center for RNA Biology. [1]

Research

Keene studies the regulation of RNA and the mechanisms of RNA-protein interactions. [2] [9] [10]

In his work on molecular genetics, he and his coworkers have examined the role of DNA and RNA-binding proteins (RBPs) in the pathogenesis of autoimmunity. [3] In the late 1970s and early 1980s he identified genomic sequences for vesicular stomatitis virus (VSV) and rabies virus (RABV), members of the Rhabdoviridae family of viruses, [11] [12] and for Ebola virus and Marburg virus from the broader group of negative-strand RNA viruses (NSRV). [13] [14] He identified the origins of defective interfering particles of negative-strand RNA viruses. [15] Through combinatorial studies of viral and bacterial systems, he has identified targets for novel pharmacological studies. [3]

Later in the 1980s, Keene identified RNA recognition motif (RRM) proteins. RRM proteins are the largest family of RNA-binding proteins and the seventh largest protein family of the human genome. RRM is a prevalent RNA-binding fold involving proteins implicated in RNA biogenesis, processing, transport, and degradation. [3] [16]

In 1987, Query and Keene first identified a B-cell epitope within the U1-70K protein. [17] [18] Keene isolated the first human autoimmune antigen and elucidated its autoimmune epitopes, the parts of an antigen to which antibodies in the immune system can bind. [3] He cloned rheumatological autoimmune protein genes. He developed a diagnostic test for systemic lupus erythematosus using recombinant antigens. [3] [19] [20]

Keene's lab has identified functions of the ELAV/Hu posttranscriptional regulators HuB, HuC and HuD and their roles and that of HuR in processes of growth, proliferation, differentiation, and immune response. [3] [21] [22] [23] The study of RNA-binding proteins such as HuR and the determination of the binding of specific sequences have informed Keene's later post-transcription theory and his coordination theory of RNA operons. [6] [3]

RNA-binding proteins appear to be implicated in the functioning of many posttranscriptional processes. As of 1994, Keene suggested that RNA-binding proteins could be involved in the regulation of messenger RNA that encode cytokines. In 2000, he was able to apply this approach to demonstrate neuronal differentiation. [1] He also introduced the first use of the RIP (ribonucleoprotein immunoprecipitation) protocol, isolating specific mRNPs using immunoprecipitation, and identifying the mRNA component with microarray or deep sequencing. This method has become a tool for the mapping of mRNA targets of specific RBPs. [5] [24]

In 2001–2002, Keene formalized the posttranscriptional operon and regulon (PTRO) model for global gene regulation. [3] [25] [26] By 2007, Keene proposed the RNA regulon hypothesis, "that mRNAs encoded by functionally related genes may be coordinately regulated as posttranscriptional RNA regulons by specific mRNP processing machineries". [27] The purpose of the RNA regulon model was to better understand post-transcriptional regulation, to answer the question "How does the cell coordinate metabolism and regulation of mRNAs encoding proteins in the same biological process so that the proteins can be coordinately produced?" [4] [28] [29]

Awards and honors

Related Research Articles

<span class="mw-page-title-main">Nucleoprotein</span> Type of protein

Nucleoproteins are proteins conjugated with nucleic acids. Typical nucleoproteins include ribosomes, nucleosomes and viral nucleocapsid proteins.

RNA-binding proteins are proteins that bind to the double or single stranded RNA in cells and participate in forming ribonucleoprotein complexes. RBPs contain various structural motifs, such as RNA recognition motif (RRM), dsRNA binding domain, zinc finger and others. They are cytoplasmic and nuclear proteins. However, since most mature RNA is exported from the nucleus relatively quickly, most RBPs in the nucleus exist as complexes of protein and pre-mRNA called heterogeneous ribonucleoprotein particles (hnRNPs). RBPs have crucial roles in various cellular processes such as: cellular function, transport and localization. They especially play a major role in post-transcriptional control of RNAs, such as: splicing, polyadenylation, mRNA stabilization, mRNA localization and translation. Eukaryotic cells express diverse RBPs with unique RNA-binding activity and protein–protein interaction. According to the Eukaryotic RBP Database (EuRBPDB), there are 2961 genes encoding RBPs in humans. During evolution, the diversity of RBPs greatly increased with the increase in the number of introns. Diversity enabled eukaryotic cells to utilize RNA exons in various arrangements, giving rise to a unique RNP (ribonucleoprotein) for each RNA. Although RBPs have a crucial role in post-transcriptional regulation in gene expression, relatively few RBPs have been studied systematically.It has now become clear that RNA–RBP interactions play important roles in many biological processes among organisms.

<span class="mw-page-title-main">Fibrillarin</span> Protein-coding gene in the species Homo sapiens

rRNA 2'-O-methyltransferase fibrillarin is an enzyme that in humans is encoded by the FBL gene.

<span class="mw-page-title-main">HNRNPA1</span> Protein-coding gene in the species Homo sapiens

Heterogeneous nuclear ribonucleoprotein A1 is a protein that in humans is encoded by the HNRNPA1 gene. Mutations in hnRNP A1 are causative of amyotrophic lateral sclerosis and the syndrome multisystem proteinopathy.

snRNP70 Protein-coding gene in the species Homo sapiens

snRNP70 also known as U1 small nuclear ribonucleoprotein 70 kDa is a protein that in humans is encoded by the SNRNP70 gene. snRNP70 is a small nuclear ribonucleoprotein that associates with U1 spliceosomal RNA, forming the U1snRNP a core component of the spliceosome. The U1-70K protein and other components of the spliceosome complex form detergent-insoluble aggregates in both sporadic and familial human cases of Alzheimer's disease. U1-70K co-localizes with Tau in neurofibrillary tangles in Alzheimer's disease.

<span class="mw-page-title-main">HNRPD</span> Protein-coding gene in the species Homo sapiens

Heterogeneous nuclear ribonucleoprotein D0 (HNRNPD) also known as AU-rich element RNA-binding protein 1 (AUF1) is a protein that in humans is encoded by the HNRNPD gene. Alternative splicing of this gene results in four transcript variants.

<span class="mw-page-title-main">HNRNPC</span> Protein-coding gene in the species Homo sapiens

Heterogeneous nuclear ribonucleoproteins C1/C2 is a protein that in humans is encoded by the HNRNPC gene.

<span class="mw-page-title-main">SYNCRIP</span> Protein-coding gene in the species Homo sapiens

Synaptotagmin-binding, cytoplasmic RNA-interacting protein (SYNCRIP), also known as heterogeneous nuclear ribonucleoprotein (hnRNP) Q or NS1-associated protein-1 (NSAP-1), is a protein that in humans is encoded by the SYNCRIP gene. As the name implies, SYNCRIP is localized predominantly in the cytoplasm. It is evolutionarily conserved across eukaryotes and participates in several cellular and disease pathways, especially in neuronal and muscular development. In humans, there are three isoforms, all of which are associated in vitro with pre-mRNAs, mRNA splicing intermediates, and mature mRNA-protein complexes, including mRNA turnover.

<span class="mw-page-title-main">Small nuclear ribonucleoprotein polypeptide A</span> Protein-coding gene in the species Homo sapiens

U1 small nuclear ribonucleoprotein A is a protein that in humans is encoded by the SNRPA gene.

<span class="mw-page-title-main">HNRPH1</span> Protein-coding gene in the species Homo sapiens

Heterogeneous nuclear ribonucleoprotein H is a protein that in humans is encoded by the HNRNPH1 gene.

<span class="mw-page-title-main">TIAL1</span> Protein-coding gene in the species Homo sapiens

Nucleolysin TIAR is a protein that in humans is encoded by the TIAL1 gene.

<span class="mw-page-title-main">HuD (protein)</span> Protein-coding gene in the species Homo sapiens

HuD otherwise known as ELAV-like protein 4 is a protein that in humans is encoded by the ELAVL4 gene.

<span class="mw-page-title-main">HNRNPR</span> Protein-coding gene in the species Homo sapiens

Heterogeneous nuclear ribonucleoprotein R is a protein that in humans is encoded by the HNRNPR gene.

<span class="mw-page-title-main">HNRPDL</span> Mammalian protein found in Homo sapiens

Heterogeneous nuclear ribonucleoprotein D-like, also known as HNRPDL, is a protein which in humans is encoded by the HNRPDL gene.

<span class="mw-page-title-main">ELAV-like protein 2</span> Protein-coding gene in the species Homo sapiens

ELAV-like protein 2 is a protein that in humans is encoded by the ELAVL2 gene.

<span class="mw-page-title-main">PTBP1</span> Protein-coding gene in the species Homo sapiens

Polypyrimidine tract-binding protein 1 is a protein that in humans is encoded by the PTBP1 gene.

Post-transcriptional regulation is the control of gene expression at the RNA level. It occurs once the RNA polymerase has been attached to the gene's promoter and is synthesizing the nucleotide sequence. Therefore, as the name indicates, it occurs between the transcription phase and the translation phase of gene expression. These controls are critical for the regulation of many genes across human tissues. It also plays a big role in cell physiology, being implicated in pathologies such as cancer and neurodegenerative diseases.

<span class="mw-page-title-main">Prp24</span>

Prp24 is a protein part of the pre-messenger RNA splicing process and aids the binding of U6 snRNA to U4 snRNA during the formation of spliceosomes. Found in eukaryotes from yeast to E. coli, fungi, and humans, Prp24 was initially discovered to be an important element of RNA splicing in 1989. Mutations in Prp24 were later discovered in 1991 to suppress mutations in U4 that resulted in cold-sensitive strains of yeast, indicating its involvement in the reformation of the U4/U6 duplex after the catalytic steps of splicing.

<span class="mw-page-title-main">RNA recognition motif</span>

RNA recognition motif, RNP-1 is a putative RNA-binding domain of about 90 amino acids that are known to bind single-stranded RNAs. It was found in many eukaryotic proteins.

<span class="mw-page-title-main">La domain</span>

In molecular biology, the La domain is a conserved protein domain.

References

  1. 1 2 3 4 5 6 "Jack Keene, PhD – Biography". Duke University. Retrieved 5 November 2019.
  2. 1 2 Doyle, Francis; Tenenbaum, Scott A. (15 April 2014). "Trans-regulation of RNA-binding protein motifs by microRNA". Frontiers in Genetics. 5: 79. doi: 10.3389/fgene.2014.00079 . PMC   4006066 . PMID   24795744.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 Hamilton, John D. (February 10, 2015). The History of Infectious Diseases At Duke University In the Twentieth Century. Lulu Publishing Services. pp. 139–140. ISBN   9781483423753 . Retrieved 23 February 2020.
  4. 1 2 Culjkovic-Kraljacic, Biljana; Borden, Katherine L. B. (5 November 2018). "The Impact of Post-transcriptional Control: Better Living Through RNA Regulons". Frontiers in Genetics. 9: 512. doi: 10.3389/fgene.2018.00512 . PMC   6230556 . PMID   30455716.
  5. 1 2 Sanford, Jeremy R.; Penalva, Luiz O. F. (29 November 2017). "The 3′ end of the story: deciphering combinatorial interactions that control mRNA fate". Genome Biology. 18 (1): 227. doi:10.1186/s13059-017-1360-6. PMC   5707901 . PMID   29187223.
  6. 1 2 3 4 5 6 7 8 Center for Oral History. "Jack D. Keene". Science History Institute .
  7. 1 2 3 4 Thackray, Arnold; Morris, Stephanie; Caruso, David (2008). Jack D. Keene, Transcript of an Interview Conducted by Arnold Thackray, Stephanie Morris, and David Caruso at Ixtapa, Mexico, and Johns Hopkins University, Baltimore, Maryland on 5 March 1989 and 23 and 25 April 2008. Philadelphia, PA: Chemical Heritage Foundation.
  8. ↑ "Jack Donald Keene". Scholars @ Duke University. Retrieved 8 February 2020.
  9. ↑ Keene, J. D. (January 2007). "Biological Clocks and the Coordination Theory of RNA Operons and Regulons". Cold Spring Harbor Symposia on Quantitative Biology. 72 (1): 157–165. doi: 10.1101/sqb.2007.72.013 . PMID   18419273.
  10. ↑ Keene, Jack D. (April 2010). "Minireview: Global Regulation and Dynamics of Ribonucleic Acid". Endocrinology. 151 (4): 1391–1397. doi:10.1210/en.2009-1250. PMC   2850242 . PMID   20332203.
  11. ↑ Wagner, Robert R. (June 29, 2013). The Rhabdoviruses. Springer Science & Business Media. pp. 139–140. ISBN   9781468470321.
  12. ↑ Keene, J. D.; Schubert, M.; Lazzarini, R. A.; Rosenberg, M. (1 July 1978). "Nucleotide sequence homology at the 3' termini of RNA from vesicular stomatitis virus and its defective interfering particles". Proceedings of the National Academy of Sciences. 75 (7): 3225–3229. Bibcode:1978PNAS...75.3225K. doi: 10.1073/pnas.75.7.3225 . PMC   392747 . PMID   210454.
  13. ↑ Deflubé, Laure R.; Cressey, Tessa N.; Hume, Adam J.; Olejnik, Judith; Haddock, Elaine; Feldmann, Friederike; Ebihara, Hideki; Fearns, Rachel; Mühlberger, Elke (23 April 2019). "Ebolavirus polymerase uses an unconventional genome replication mechanism". Proceedings of the National Academy of Sciences. 116 (17): 8535–8543. doi: 10.1073/pnas.1815745116 . PMC   6486738 . PMID   30962389.
  14. ↑ Kiley, Michael P.; Wilusz, Jeffrey; Mc Cormick, Joseph B.; Keene, Jack D. (March 1986). "Conservation of the 3′ terminal nucleotide sequences of Ebola and Marburg virus". Virology. 149 (2): 251–254. doi:10.1016/0042-6822(86)90127-3. PMID   3946083.
  15. ↑ Lazzarini, Robert A.; Keene, Jack D.; Schubert, Manfred (October 1981). "The origins of defective interfering particles of the negative-strand RNA viruses". Cell. 26 (2): 145–154. doi:10.1016/0092-8674(81)90298-1. PMID   7037195.
  16. ↑ Loerch, Sarah; Kielkopf, Clara L. (September 2015). "Dividing and Conquering the Family of RNA Recognition Motifs: A Representative Case Based on hnRNP L". Journal of Molecular Biology. 427 (19): 2997–3000. doi:10.1016/j.jmb.2015.06.009. PMC   4820351 . PMID   26101840.
  17. ↑ Kattah, Nicole H.; Kattah, Michael G.; Utz, Paul J. (January 2010). "The U1-snRNP complex: structural properties relating to autoimmune pathogenesis in rheumatic diseases". Immunological Reviews. 233 (1): 126–145. doi:10.1111/j.0105-2896.2009.00863.x. PMC   3074261 . PMID   20192997.
  18. ↑ Query, C (October 1987). "A human autoimmune protein associated with U1 RNA contains a region of homology that is cross-reactive with retroviral p30gag antigen". Cell. 51 (2): 211–220. doi:10.1016/0092-8674(87)90148-6. PMC   3074261 . PMID   2959371.
  19. ↑ Habets, WJ; Hoet, MH; Sillekens, PT; De Rooij, DJ; Van de Putte, LB; Van Venrooij, WJ (May 1989). "Detection of autoantibodies in a quantitative immunoassay using recombinant ribonucleoprotein antigens". Clinical and Experimental Immunology. 76 (2): 172–7. PMC   1541836 . PMID   2527098.
  20. ↑ Chambers, J. C.; Keene, J. D. (1 April 1985). "Isolation and analysis of cDNA clones expressing human lupus La antigen". Proceedings of the National Academy of Sciences. 82 (7): 2115–2119. Bibcode:1985PNAS...82.2115C. doi: 10.1073/pnas.82.7.2115 . PMC   397503 . PMID   3856888.
  21. ↑ Simone, Laura E; Keene, Jack D (February 2013). "Mechanisms coordinating ELAV/Hu mRNA regulons". Current Opinion in Genetics & Development. 23 (1): 35–43. doi:10.1016/j.gde.2012.12.006. PMC   3617084 . PMID   23312841.
  22. ↑ Bevilacqua, Annamaria; Ceriani, Maria Cristina; Capaccioli, Sergio; Nicolin, Angelo (June 2003). "Post-transcriptional regulation of gene expression by degradation of messenger RNAs". Journal of Cellular Physiology. 195 (3): 356–372. doi: 10.1002/jcp.10272 . PMID   12704645.
  23. ↑ Mansfield, Kyle D.; Keene, Jack D. (March 2012). "Neuron-specific ELAV/Hu proteins suppress HuR mRNA during neuronal differentiation by alternative polyadenylation". Nucleic Acids Research. 40 (6): 2734–2746. doi:10.1093/nar/gkr1114. PMC   3315332 . PMID   22139917.
  24. ↑ Keene, J. D. (19 June 2001). "Ribonucleoprotein infrastructure regulating the flow of genetic information between the genome and the proteome". Proceedings of the National Academy of Sciences. 98 (13): 7018–7024. Bibcode:2001PNAS...98.7018K. doi: 10.1073/pnas.111145598 . PMC   34616 . PMID   11416181.
  25. ↑ Aparicio, Luis A.; Abella, Vanessa; Valladares, Manuel; Figueroa, Angélica (29 May 2013). "Posttranscriptional regulation by RNA-binding proteins during epithelial-to-mesenchymal transition". Cellular and Molecular Life Sciences. 70 (23): 4463–4477. doi: 10.1007/s00018-013-1379-0 . PMC   3827902 . PMID   23715860.
  26. ↑ Keene, Jack D. (July 2007). "RNA regulons: coordination of post-transcriptional events" (PDF). Nature Reviews Genetics. 8 (7): 533–543. doi:10.1038/nrg2111. PMID   17572691 . Retrieved 8 February 2020.
  27. ↑ Wang, Li; Miao, Yi-Liang; Zheng, Xiaofeng; Lackford, Brad; Zhou, Bingying; Han, Leng; Yao, Chengguo; Ward, James M.; Burkholder, Adam; Lipchina, Inna; Fargo, David C.; Hochedlinger, Konrad; Shi, Yongsheng; Williams, Carmen J.; Hu, Guang (December 2013). "The THO Complex Regulates Pluripotency Gene mRNA Export and Controls Embryonic Stem Cell Self-Renewal and Somatic Cell Reprogramming". Cell Stem Cell. 13 (6): 676–690. doi:10.1016/j.stem.2013.10.008. PMC   3962795 . PMID   24315442.
  28. ↑ Pulendran, Bali; Katsikis, Peter D.; Schoenberger, Stephen P., eds. (August 19, 2011). Crossroads between Innate and Adaptive Immunity III. Springer Science & Business Media. pp. 1–3. ISBN   9781441956323 . Retrieved 24 February 2020.
  29. ↑ Larsson, Ola; Nadon, Robert (April 1, 2009). "Gene Expression - Time to change point of view?". In Harding, Stephen (ed.). Biotechnology & Genetic Engineering Reviews. Vol. 25. Nottingham University Press. pp. 86–87. ISBN   9781904761662.
  30. ↑ "Jack D. Keene, Ph.D." The Pew Charitable Trusts. Retrieved 23 February 2020.
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