Steve A. Kay

Last updated

Steve Kay

FRS
BornOctober 4
Jersey
Nationality British, American since 2003
EducationUniversity of Bristol, UK
Known for chronobiology, genomics
AwardsThomson Reuters Highly Cited Researcher, ASPB Award for the Martin Gibbs Medal, AAAS Fellow, Member of the National Academy of Sciences USA, Science Breakthroughs of the Year 2002, Science Breakthroughs of the Year 1998, Science Breakthroughs of the Year 1997

Steve A. Kay FRS is a British-born chronobiologist who mainly works in the United States. Dr. Kay has pioneered methods to monitor daily gene expression in real time and characterized circadian gene expression in plants, flies and mammals. In 2014, Steve Kay celebrated 25 years of successful chronobiology research at the Kaylab 25 Symposium, joined by over one hundred researchers with whom he had collaborated with or mentored. [1] Dr. Kay, a member of the National Academy of Sciences, U.S.A., briefly served as president of The Scripps Research Institute. [2] and is currently a professor at the University of Southern California. He also served on the Life Sciences jury for the Infosys Prize in 2011.

Contents

Life

Early life and influences

Steve A. Kay was raised on the Isle of Jersey off the coast of Normandy. As a young child, he was fascinated by marine creatures exposed during low tide on Jersey island. His interest in biology deepened when an elementary teacher brought a microscope from mainland England into his small classroom. He spent hours looking through the microscope at swimming critters in pond water, amazed by "what was in pond water, or what the edges of a torn piece of paper looked like." [3] By his early teens, Steve Kay knew that biology would be his lifelong passion and aimed to get a PhD. Years later, when his mother died of a progressive motor neuron disease in 2006, Steve Kay was motivated to study a mouse mutant he co-discovered that modeled the disease his mother had. Thus, a tribute to his mother has led to the discovery of the gene Listerin, Ltn1, E3 ubiquitin ligase and its effect on motor and sensory neuron degeneration. [3]

Education and scientific pursuits

In 1981, Steve Kay earned his bachelor's degree in Biochemistry at University of Bristol, UK. He stayed there in the Trevor Griffiths lab and received his PhD in 1985 exploring the light regulation of chlorophyll synthesis in plants. [3] Kay learned that light changed gene expression, [4] and that circadian clock was also regulating transcription on a daily basis. He would later spend more than two decades pursuing these circadian clocks. Following Griffiths' advice, Kay moved to the United States and worked as a postdoc in the Nam-Hai Chua lab at Rockefeller University. It was at the Nam-Hai Chua lab working with another postdoc named Ferenc Nagy that Kay stumbled upon the discovery that the chlorophyll binding gene CAB was regulated by a circadian clock. [3] In 1989, Kay was appointed to his first faculty position as an assistant professor at Rockefeller University. While there, he collaborated with Michael W. Young to identify fly PER gene homologues, which did not exist. Kay then developed glowing Arabidopsis thaliana plants to screen for circadian rhythm mutants, with the help of his student Andrew Millar, [3] and subsequently identified TOC1, the first clock gene identified in plants.

He moved several times and became an associate professor in the biology department at the University of Virginia in 1996 where he joined the NSF Center for Biological Timing. 4 years later he moved to The Scripps Research Institute in La Jolla, Ca. There, Kay collaborated with Jeffrey C. Hall and discovered a cryptochrome mutant in fruit flies, also demonstrating that clock genes were distributed all over the body, which was named one of Science's top 10 breakthroughs in 1997. [3] Kay also teamed up with Joe Takahashi to identify fly's CLOCK gene and its binding partner dBMAL1 and complete the transcription-translation feedback loop in flies in 1998.

In 1999, Kay established his second lab adjacent to Scripps Research Institute at the Genomics Institute of the Novartis Research Foundation to initiate new work on the mammalian clock. He and his postdoctoral fellow John B. Hogenesch, realized that in order to discover novel mammalian clock genes one would have to leverage high throughput genomics techniques that were being developed at the time. [3] In 2002, Kay's group identified the novel photoreceptor melanopsin (Opn4) and how it worked in conjunction with the visual photoreceptors. [3] Kay's work, along with others in the field, on melanopsin was named one of "Science's" top 10 breakthroughs that year. Kay and Hogenesch also collaborated with Takahashi to define the mammalian circadian transcription and the large scale orchestration of gene expression by the circadian clocks in most tissues throughout the body. [3]

In 2001, Kay served as director for the Institute for Childhood and Neglected Diseases at the Scripps Research Institute. [5] He also served as professor and chairman there in subsequent years. In addition to his academic experiences, Kay also founded biotechnology companies like Phenomix Corporation in 2003. [5] In 2007, Dr. Kay became professor and then the dean of the biology department at the UC San Diego. From 2012 to 2015, he served as a professor and the Dean of Dornsife College of Letters, Arts and Sciences at the University of Southern California (USC). [5]

In September 2015, he was named president of The Scripps Research Institute. [2] In 2016, he was re-appointed to the University of Southern California (USC). [6]

Scientific contributions to circadian rhythms

Plants

In 1985, Kay and his colleagues found that the Cab gene was under circadian control in wheat and transgenic tobacco plants during his postdoctoral research. In 1991, Kay extended this research into a suitable model plant, Arabidopsis thaliana and found that Cab mRNA levels are also under circadian control in Arabidopsis . [7] He then developed Cab2:luc fusion, the fusion of luciferase open reading frame downstream of the Cab2 promoter region, as a marker for monitoring the circadian phenotype. This fusion marker was widely used in later studies and contributed enormously to the understanding of circadian rhythm regulation in Arabidopsis . [8]

Based on this Cab:luc fusion technology, Kay set up luciferase imaging assays for large scale forward genetics screening and identified the first short period mutant of TOC1 gene. TOC1 was proved to be a core clock gene in Arabidopsis and was cloned by Kay lab after a long period of time [9] Kay also revealed the biochemical function of TOC1 and found that TOC1 and LHY/CCA1 reciprocally regulate each other, and further studied the mechanism of this regulation. [10]

Kay identified ELF3, GI, Lux, CHE and PRRs as core clock genes and studied their role in the circadian regulation loop. [11] He also profiled clock controlled genes (ccg) in Arabidopsis with several technologies and identified key pathways temporally controlled by circadian clock. His work on functional analyses of core clock genes, as well as ccg, successfully connected circadian rhythm with the control of development, like seedling, growth and flowering. His work on these clock genes contributed significantly to the understanding of repression-based clock regulation loops in plants, which is distinct to the ones in animals that are composed of both positive and negative elements. [12]

Kay discovered the mechanism of seasonal time and day-length measurement and flowering time determination in Arabidopsis through the GI/FKF1-CO-FT pathway. [13]

Kay found evidence that there are multiple phototransduction pathways, and contributed to the discovery and functional analysis of many photoreceptors, including phytochrome, cryptochrome, ZTL and LKP2 and their roles in circadian rhythms. [14]

Flies

Kay applied the first clock gene fusion, Per:luc, in Drosophila melanogaster which allows monitoring of its rhythm at the single animal level. Per:luc fusion also helped him understand the phase relationship in mRNA and protein oscillation. He further improved the mathematical method of bioluminescence analysis and made the results quantified. [15] In 1997, his Per promoter driven Green Fluorescent Protein (GFP) study suggested that Per is widely expressed throughout the fly body in a rhythmic pattern, and all body parts are capable of light perception. This is one of the first pieces of evidence for a peripheral self-sustaining circadian clock. [16] In 1998, he proposed the translational transcriptional feedback loop model of the circadian clock in flies, analogous to other labs that proposed a same model in mammals and fungi.

Kay discovered that cryptochrome is the circadian photoreceptor that directly acts with and sequesters TIM in response to light. [17]

Kay did one of the pioneering microarray analyses to study clock controlled genes (ccg), and revealed tissue-specific nature of circadian rhythms by analyzing the ccg of heads and bodies separately. [18]

Mice

Kay began his extensive research on mice in 1999 at the Genomics Institute of the Novartis Research Foundation, with a primary focus on melanopsin (Opn4) and visual photoreceptors. It was here, with the use of automation and large-scale genomics technology, that Kay and collaborating colleagues found that the mammalian clock consisted of more than just one feedback loop.

In 2002, Kay and his team were able to show the role of melanopsin, a photosensitive photopigment in retinal ganglion cells, in detecting light for the master circadian oscillator located in the suprachiasmatic nucleus (SCN) in the hypothalamus of the brain. Both melanopsin and visual photoreceptors, such as rods and cones, were required for entrainment. However, removing each individually did not result in total blindness in mice, as they retained non-visual photoreception. [19]

The enzyme luciferase was utilized by Kay's lab to research clock gene expression in single culture cells and revealed that a variety of cells, including those of the liver and fibroblasts, demonstrate circadian rhythm. [20] As time went on, these rhythms became increasingly out of phase as local oscillators desynchronized and each cell expressed their own pace. In 2007, these findings demonstrated the need to examine single-cell phenotypes along with behaviors of experimental clock mutants.

In 2009, inspired by his mother's fatal motor neuron disease, Kay and some colleagues performed a study manipulating the ubiquitin ligase protein Listerin in mice which led to the conclusion that mutations in Listerin caused neurodegeneration. [21]

Humans

Kay's research on intercellular networks has the potential to contribute to drug therapies by identifying compounds that affect the circadian pathways. [22] His findings and analyses of this mammalian oscillator contribute to our medical understanding of how the clock controls downstream processes and holds clinical significance as a variety of diseases and biological processes are involved, such as aging, immune response, and metabolism. [23]

For instance, diabetes and the circadian clock may correlate based on the findings of circadian expression in the liver and glucose output. Using a cell-cased circadian phenotypic screen, Kay and a team of chronobiologist researchers identified a small molecule, KL001, that interacts with cryptochrome to prevent ubiquitin-dependent degradation, which results in a longer circadian period. KL001-mediated cryptochrome stabilization (of both CRY1 and CRY2) was found to restrain glucagon-activated gluconeogenesis. These findings bear the potential to aid in the development of circadian-based diabetic therapeutics. [24]

Circadian clocks have also been shown to influence cancer treatments, where circadian disruption accelerates processes and drug responses are affected by the time of administration with respect to the circadian cycle. [25]

Positions and honors

[5]

Notable publications

Related Research Articles

<span class="mw-page-title-main">Circadian rhythm</span> Natural internal process that regulates the sleep-wake cycle

A circadian rhythm, or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism and responds to the environment. Circadian rhythms are regulated by a circadian clock whose primary function is to rhythmically co-ordinate biological processes so they occur at the correct time to maximise the fitness of an individual. Circadian rhythms have been widely observed in animals, plants, fungi and cyanobacteria and there is evidence that they evolved independently in each of these kingdoms of life.

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

Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinal proteins called opsins and encoded by the gene Opn4. In the mammalian retina, there are two additional categories of opsins, both involved in the formation of visual images: rhodopsin and photopsin in the rod and cone photoreceptor cells, respectively.

A circadian clock, or circadian oscillator, is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time.

<span class="mw-page-title-main">Cryptochrome</span> Class of photoreceptors in plants and animals

Cryptochromes are a class of flavoproteins found in plants and animals that are sensitive to blue light. They are involved in the circadian rhythms and the sensing of magnetic fields in a number of species. The name cryptochrome was proposed as a portmanteau combining the chromatic nature of the photoreceptor, and the cryptogamic organisms on which many blue-light studies were carried out.

The repressilator is a genetic regulatory network consisting of at least one feedback loop with at least three genes, each expressing a protein that represses the next gene in the loop. In biological research, repressilators have been used to build cellular models and understand cell function. There are both artificial and naturally-occurring repressilators. Recently, the naturally-occurring repressilator clock gene circuit in Arabidopsis thaliana and mammalian systems have been studied.

Photoreceptor proteins are light-sensitive proteins involved in the sensing and response to light in a variety of organisms. Some examples are rhodopsin in the photoreceptor cells of the vertebrate retina, phytochrome in plants, and bacteriorhodopsin and bacteriophytochromes in some bacteria. They mediate light responses as varied as visual perception, phototropism and phototaxis, as well as responses to light-dark cycles such as circadian rhythm and other photoperiodisms including control of flowering times in plants and mating seasons in animals.

<span class="mw-page-title-main">Michael Rosbash</span> American geneticist and chronobiologist (born 1944)

Michael Morris Rosbash is an American geneticist and chronobiologist. Rosbash is a professor and researcher at Brandeis University and investigator at the Howard Hughes Medical Institute. Rosbash's research group cloned the Drosophila period gene in 1984 and proposed the Transcription Translation Negative Feedback Loop for circadian clocks in 1990. In 1998, they discovered the cycle gene, clock gene, and cryptochrome photoreceptor in Drosophila through the use of forward genetics, by first identifying the phenotype of a mutant and then determining the genetics behind the mutation. Rosbash was elected to the National Academy of Sciences in 2003. Along with Michael W. Young and Jeffrey C. Hall, he was awarded the 2017 Nobel Prize in Physiology or Medicine "for their discoveries of molecular mechanisms controlling the circadian rhythm".

John B. Hogenesch is an American chronobiologist and Professor of Pediatrics at the Cincinnati Children's Hospital Medical Center. The primary focus of his work has been studying the network of mammalian clock genes from the genomic and computational perspective to further the understanding of circadian behavior. He is currently the Deputy Director of the Center for Chronobiology, an Ohio Eminent Scholar, and Professor of Pediatrics in the Divisions of Perinatal Biology and Immunobiology at the Cincinnati Children's Hospital Medical Center.

Circadian Clock Associated 1 (CCA1) is a gene that is central to the circadian oscillator of angiosperms. It was first identified in Arabidopsis thaliana in 1993. CCA1 interacts with LHY and TOC1 to form the core of the oscillator system. CCA1 expression peaks at dawn. Loss of CCA1 function leads to a shortened period in the expression of many other genes.

LUX or Phytoclock1 (PCL1) is a gene that codes for LUX ARRHYTHMO, a protein necessary for circadian rhythms in Arabidopsis thaliana. LUX protein associates with Early Flowering 3 (ELF3) and Early Flowering 4 (ELF4) to form the Evening Complex (EC), a core component of the Arabidopsis repressilator model of the plant circadian clock. The LUX protein functions as a transcription factor that negatively regulates Pseudo-Response Regulator 9 (PRR9), a core gene of the Midday Complex, another component of the Arabidopsis repressilator model. LUX is also associated with circadian control of hypocotyl growth factor genes PHYTOCHROME INTERACTING FACTOR 4 (PIF4) and PHYTOCHROME INTERACTING FACTOR 5 (PIF5).

Pseudo-response regulator (PRR) refers to a group of genes that regulate the circadian oscillator in plants. There are four primary PRR proteins that perform the majority of interactions with other proteins within the circadian oscillator, and another (PRR3) that has limited function. These genes are all paralogs of each other, and all repress the transcription of Circadian Clock Associated 1 (CCA1) and Late Elongated Hypocotyl (LHY) at various times throughout the day. The expression of PRR9, PRR7, PRR5 and TOC1/PRR1 peak around morning, mid-day, afternoon and evening, respectively. As a group, these genes are one part of the three-part repressilator system that governs the biological clock in plants.

The Late Elongated Hypocotyl gene (LHY), is an oscillating gene found in plants that functions as part of their circadian clock. LHY encodes components of mutually regulatory negative feedback loops with Circadian Clock Associated 1 (CCA1) in which overexpression of either results in dampening of both of their expression. This negative feedback loop affects the rhythmicity of multiple outputs creating a daytime protein complex. LHY was one of the first genes identified in the plant clock, along with TOC1 and CCA1. LHY and CCA1 have similar patterns of expression, which is capable of being induced by light. Single loss-of-function mutants in both genes result in seemingly identical phenotypes, but LHY cannot fully rescue the rhythm when CCA1 is absent, indicating that they may only be partially functionally redundant. Under constant light conditions, CCA1 and LHY double loss-of-function mutants fail to maintain rhythms in clock-controlled RNAs.

Transcription-translation feedback loop (TTFL) is a cellular model for explaining circadian rhythms in behavior and physiology. Widely conserved across species, the TTFL is auto-regulatory, in which transcription of clock genes is regulated by their own protein products.

Jay Dunlap is an American chronobiologist and photobiologist who has made significant contributions to the field of chronobiology by investigating the underlying mechanisms of circadian systems in Neurospora, a fungus commonly used as a model organism in biology, and in mice and mammalian cell culture models. Major contributions by Jay Dunlap include his work investigating the role of frq and wc clock genes in circadian rhythmicity, and his leadership in coordinating the whole genome knockout collection for Neurospora. He is currently the Nathan Smith Professor of Molecular and Systems Biology at the Geisel School of Medicine at Dartmouth. He and his colleague Jennifer Loros have mentored numerous students and postdoctoral fellows, many of whom presently hold positions at various academic institutions.

Carla Beth Green is an American neurobiologist and chronobiologist. She is a professor in the Department of Neuroscience and a Distinguished Scholar in Neuroscience at the University of Texas Southwestern Medical Center. She is the former president of the Society for Research on Biological Rhythms (SRBR), as well as a satellite member of the International Institute for Integrative Sleep Medicine at the University of Tsukuba in Japan.

Dmitri Nusinow is an American chronobiologist who studies plant circadian rhythms. He was born on November 7, 1976, in Inglewood, California. He currently resides in St. Louis, and his research focus includes a combination of molecular, biochemical, genetic, genomic, and proteomic tools to discover the molecular connections between signaling networks, circadian oscillators, and specific outputs. By combining these methods, he hopes to apply the knowledge elucidated from the Arabidopsis model to other plant species.

EARLY FLOWERING 3 (ELF3) is a plant-specific gene that encodes the hydroxyproline-rich glycoprotein and is required for the function of the circadian clock. ELF3 is one of the three components that make up the Evening Complex (EC) within the plant circadian clock, in which all three components reach peak gene expression and protein levels at dusk. ELF3 serves as a scaffold to bind EARLY FLOWERING 4 (ELF4) and LUX ARRHYTHMO (LUX), two other components of the EC, and functions to control photoperiod sensitivity in plants. ELF3 also plays an important role in temperature and light input within plants for circadian clock entrainment. Additionally, it plays roles in light and temperature signaling that are independent from its role in the EC.

Elaine Munsey Tobin is a professor of molecular, cell, and developmental biology at the University of California, Los Angeles (UCLA). Tobin is recognized as a Pioneer Member of the American Society of Plant Biologists (ASPB).

The chlorophyll a/b-binding protein gene, otherwise known as the CAB gene, is one of the most thoroughly characterized clock-regulated genes in plants. There are a variety of CAB proteins that are derived from this gene family. Studies on Arabidopsis plants have shed light on the mechanisms of biological clocks under the regulation of CAB genes. Dr. Steve Kay discovered that CAB was regulated by a circadian clock, which switched the gene on in the morning and off in the late afternoon. The genes code for proteins that associate with chlorophyll and xanthophylls. This association aids the absorption of sunlight, which transfers energy to photosystem II to drive photosynthetic electron transport.

Stacey Harmer is a chronobiologist whose work centers on the study of circadian rhythms in plants. Her research focuses on the molecular workings of the plant circadian clock and its influences on plant behaviors and physiology. She is a professor in the Department of Plant Biology at the University of California, Davis.

References

  1. ↑ Tripathi, Pratheek (2014). "Chronobiology: Past, Present and Future". ASPB Plant Science Blog.
  2. 1 2 "Scripps Research Institute Names Peter Schultz as CEO, Steve Kay as President".
  3. 1 2 3 4 5 6 7 8 9 Trivedi, Bijal (2009). "Profile of Steve Kay". PNAS. 106 (43): 18051–18053. Bibcode:2009PNAS..10618051T. doi: 10.1073/pnas.0910583106 . PMC   2775350 . PMID   19846773.
  4. ↑ Smieszek, Sandra (2014). "Steve Kay". ASPB News. 41 (2): 13.
  5. 1 2 3 4 Open Source Initiative Contributor. "Steve. A. Kay. Ph.D." Archived 2015-02-26 at the Wayback Machine . Retrieved on 08 April 2015.
  6. ↑ Fikes, Bradley J. "Scripps Research president returns to USC". sandiegouniontribune.com. Retrieved 29 September 2017.
  7. ↑ Atkins, K.A. & Dodd, A.N. (2014). "Circadian Regulation of Chloroplasts". Current Opinion in Plant Biology. 21: 43–50. doi:10.1016/j.pbi.2014.06.008. PMID   25026538.
  8. ↑ McClung, C.R. (2006). "Plant Circadian Rhythms". The Plant Cell. 18 (4): 792–803. doi:10.1105/tpc.106.040980. PMC   1425852 . PMID   16595397.
  9. ↑ Dunlap, J.C. (1999). "Molecular Bases for Circadian Clocks". Cell. 96 (2): 271–290. doi: 10.1016/S0092-8674(00)80566-8 . PMID   9988221. S2CID   14991100.
  10. ↑ Nagel, D. H. & Kay, S. A. (2012). "Complexity in the Wiring and Regulation of Plant Circadian Networks". Current Biology. 22 (16): 648–657. doi:10.1016/j.cub.2012.07.025. PMC   3427731 . PMID   22917516.
  11. ↑ Imaizumi, T. (2010). "Arabidopsis Circadian Clock and Photoperiodism:Time to Think about Location". Current Opinion in Plant Biology. 13 (1): 83–89. doi:10.1016/j.pbi.2009.09.007. PMC   2818179 . PMID   19836294.
  12. ↑ Pokhilko, A.; et al. (2012). "The Clock Gene Circuit in Arabidopsis Includes a Repressilator with Additional Feedback Loops". Molecular Systems Biology. 8: 574. doi:10.1038/msb.2012.6. PMC   3321525 . PMID   22395476.
  13. ↑ Boss, P. K., Bastow, R. M., Mylne, J. S. & Dean, C. (2004). "Multiple pathways in the decision to flower: enabling, promoting, and resetting". The Plant Cell. 16 (Suppl): S18–S31. doi:10.1105/tpc.015958. PMC   2643402 . PMID   15037730.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ↑ Chen, M., Chory, J. & Fankhauser, C. (2004). "Light signal transduction in higher plants". Annual Review of Genetics. 38: 87–117. doi:10.1146/annurev.genet.38.072902.092259. PMID   15568973.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ↑ Contag, C. H. & Bachmann, M. H. (2002). "Advances in In Vivo Bioluminescence Imaging of Gene Expression". Annual Review of Biomedical Engineering. 4: 235–260. doi:10.1146/annurev.bioeng.4.111901.093336. PMID   12117758.
  16. ↑ Hastings, M. H., Reddy, A. B. & Maywood, E. S. (2003). "A Clockwork Web: Circadian Timing in Brain and Periphery, in Health and Disease". Nature Reviews Neuroscience. 4 (8): 649–661. doi:10.1038/nrn1177. PMID   12894240. S2CID   205499642.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ↑ Young, M. W. & Kay, S. A. (2001). "Time Zones: A Comparative Genetics of Circadian Clocks". Nature Reviews Genetics. 2 (9): 702–715. doi:10.1038/35088576. PMID   11533719. S2CID   13286388.
  18. ↑ Hardin, P. E. (2005). "The Circadian Timekeeping System of Drosophila". Current Biology. 15 (17): 714–R722. doi: 10.1016/j.cub.2005.08.019 . PMID   16139204. S2CID   14904841.
  19. ↑ Satchidananda Panda, Ignacio Provencio, Daniel C. Tu, Susana S. Pires, Mark D. Rollag, Ana Maria Castrucci, Mathew T. Pletcher, Trey K. Sato, Tim Wiltshire, Mary Andahazy, Steve A. Kay, Russell N. Van Gelder and John B. Hogenesch (2003). "Melanopsin Is Required for Non-Image-Forming Photic Responses in Blind Mice". Science. 301 (5632): 525–527. Bibcode:2003Sci...301..525P. doi:10.1126/science.1086179. PMID   12829787. S2CID   37600812.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ↑ Charna Dibner; Ueli Schibler & Urs Albrecht (2010). "The Mammalian Circadian Timing System: Organization and Coordination of Central and Peripheral Clocks" (PDF). Annual Review of Physiology. 72: 517–549. doi:10.1146/annurev-physiol-021909-135821. PMID   20148687.
  21. ↑ Mario H. Bengtson & Claudio A.P. Joazeiro (2010). "Listerin-Dependent Nascent Protein Ubiquitination Relies on Ribosome Subunit Dissociation". Nature. 467 (7314): 470–473. doi:10.1038/nature09371. PMC   2988496 . PMID   20835226.
  22. ↑ Hirota T, et al. (2008). "A Chemical Biology Approach Reveals Period Shortening of the Mammalian Circadian Clock by Specific Inhibition of GSK-3β". Proceedings of the National Academy of Sciences USA. 105 (52): 20746–20751. Bibcode:2008PNAS..10520746H. doi: 10.1073/pnas.0811410106 . PMC   2606900 . PMID   19104043.
  23. ↑ Doherty, Colleen, Kay, Steve (2012). "Circadian Surprise- It's Not All About Transcription". Science. 338 (6105): 338–340. Bibcode:2012Sci...338..338D. doi:10.1126/science.1230008. PMID   23087238. S2CID   37498090.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ↑ Hirota T; Lee JW; St. John PC; Sawa M (2012). "Identification of small molecule activators in cryptochrome". Science. 337 (6098): 1094–1097. Bibcode:2012Sci...337.1094H. doi:10.1126/science.1223710. PMC   3589997 . PMID   22798407.
  25. ↑ Francis Lévi; Alper Okyar; Sandrine Dulong; Pasquale F. Innominato & Jean Clairambault (2010). "Circadian Timing in Cancer Treatments". Annual Review of Pharmacology and Toxicology. 50: 377–421. doi:10.1146/annurev.pharmtox.48.113006.094626. PMID   20055686.
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