Jeffrey L. Price

Last updated
Jeffrey Price
Born1958
New York City, New York
Alma materUndergraduate: College of William and Mary
Ph.D.: Johns Hopkins University
Known for Circadian rhythms research
Scientific career
Fields Chronobiology, Neurology, Cognitive Neuroscience
Institutions University of Missouri-Kansas City
Member of Society for Research on Biological Rhythms
Academic advisors Michael W. Young
Website sbs.umkc.edu

Jeffrey L. Price (born 1958) is an American researcher and author in the fields of circadian rhythms and molecular biology. His chronobiology work with Drosophila melanogaster has led to the discoveries of the circadian genes timeless (tim) and doubletime (dbt), and the doubletime regulators spaghetti (SPAG) and bride of doubletime (BDBT).

Contents

Background and education

Price was born in New York City and raised in New Jersey and Virginia. [1] He graduated from the College of William and Mary with a Bachelor of Science degree in biology, and later received his Ph.D. in biology from Johns Hopkins University. He completed his postdoctoral training in Taiwan, Republic of China, and in the lab of Michael Young at Rockefeller University through the Howard Hughes Medical Institute. Price is currently an associate professor in the School of Biological Sciences at University of Missouri-Kansas City, and an associate professor in the department of Neurology and Cognitive Neuroscience at the University of Missouri–Kansas City School of Medicine. [2]

Research interests

Price's research centers around the molecular mechanisms of circadian rhythms, using Drosophila melanogaster as model organisms. He is specifically interested in the role of protein kinases in clock function, and using forward genetics screens Price has contributed to the identification and characterization of many critical elements of the Drosophila circadian clock.

The molecular circadian clock of D. melanogaster can be described as a feedback loop of transcription and translation, in which the proteins CLOCK and CYCLE act as transcriptional activators of the period and timeless genes. Their protein products, PER and TIM, respectively, dimerize and translocate to the nucleus after phosphorylation by DBT. In the nucleus, PER/TIM heterodimers bind to and suppress CLK/CYC heterodimers to inhibit the transcription of period and timeless, resulting in daily oscillations of PER and TIM. [3] DBT is itself regulated by BDBT and SPAG, which stimulate its kinase activity toward PER and increase the cytoplasmic stability of DBT, respectively.

Timeline of selected major research contributions

Timeless

In 1994, Price, together with Amita Sehgal, identified the timeless gene through forward genetics mutagenesis screens. A mutant Drosophila line was generated displaying arrythmia in time of eclosion and per mRNA cycling, reliable phase markers for the Drosophila circadian clock. [4] Price and Seghal mapped the mutations to chromosome 2 and termed the novel gene timeless. Leslie Vosshall, one of their collaborators, later noted that tim mutants were unable to localize PER protein to the nucleus, suggesting an interaction between PER and TIM. [5] Price later contributed to the characterization of six mutant tim alleles altering circadian rhythm, providing further evidence for its role in clock function. [6]

Double-time

In 1998, Price, together with Justin Blau and Adrian Rothenfluh, characterized three mutant alleles of another novel clock gene, doubletime, or dbt, through forward genetics mutagenesis screens and mapped the mutations to chromosome 3. The mutations, termed dbtS, dbtL, and dbtP, shortened (dbtS) or lengthened (dbtL) circadian rhythms in Drosophila. DbtP was lethal to pupae, but Price and Blau noted that mutant strains of Drosophila larvae harboring homozygous dbtP mutations also sustained loss of rhythms in PER and TIM protein levels, as well as constitutive accumulation of PER protein. [7] These results suggested that the normal function of DBT is to reduce the stability of PER protein monomers through phosphorylation status. The identification of double-time provided a crucial explanation for the observed 4-6-hour delay between peak per mRNA levels and peak PER protein levels in the Drosophila clock.

In addition to studying kinase function in D. melanogaster, Price studies the role of protein kinases in vertebrate clocks. Evolutionary analysis has shown DBT has orthologs in the mammalian genome, specifically CK1ε and CK1δ of the Casein kinase 1 family of kinases, suggesting that the mammalian clock may contain kinases with similar function. [8] [9] The mammalian clock has since been well characterized, and both CK1ε and CK1δ appear to perform a similar function to DBT, though CK1δ may have a larger effect on clock function.

Bride of Double-time

In 2013, Price's lab identified a noncanonical FK506-binding protein named Bride of Double-time (BDBT), which interacts with DBT protein kinase. In his experiment, RNA interference (RNAi), which reduced BDBT expression, resulted in long periods and arrhythmicity of locomotion, as well as high levels of hypophosphorylated nuclear PER and phosphorylated DBT. [10] These results demonstrated a role for BDBT in the circadian clock. When BDBT was overexpressed, Price found that the phosphorylation and DBT-dependent degradation of PER increased, suggesting that BDBT stimulates DBT circadian activity toward PER. [10] In addition, BDBT was shown to rhythmically accumulate in PER and DBT-dependent cytosolic foci in the fly eye. Price's lab established BDBT as a mediator of DBT's effects on PER, which regulates PER nuclear accumulation in discrete foci In photoreceptors. [10] In 2015, Price's lab noted that DBT proteins lacking a nuclear localization signal (NLS) failed to interact with BDBT, suggesting that this interaction is mediated by the NLS. [11]

Spaghetti

In 2015, Price identified an upstream regulator of DBT named spaghetti, encoding the SPAG protein. SPAG antagonizes DBT autophosphorylation, increasing the stability of DBT during the day by delaying proteasomal degradation. Using RNAi, Price found that SPAG knockdowns in Drosophila caused either an increase in period or arhythmicity, as well as reduction in cellular levels of DBT. [12] SPAG also has a role in neurodegeneration, as flies with reduced SPAG experienced increased levels of activated caspase proteins in the optic lobes, resulting in neurodegeneration through apoptosis when human tau is also expressed in the eye. [12] [13]

Related Research Articles

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

The Casein kinase 1 family of protein kinases are serine/threonine-selective enzymes that function as regulators of signal transduction pathways in most eukaryotic cell types. CK1 isoforms are involved in Wnt signaling, circadian rhythms, nucleo-cytoplasmic shuttling of transcription factors, DNA repair, and DNA transcription.

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

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

Timeless (tim) is a gene in multiple species but is most notable for its role in Drosophila for encoding TIM, an essential protein that regulates circadian rhythm. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation negative feedback loop involving the period (per) gene and its protein.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

<span class="mw-page-title-main">PER2</span> Protein-coding gene in the species Homo sapiens

PER2 is a protein in mammals encoded by the PER2 gene. PER2 is noted for its major role in circadian rhythms.

<span class="mw-page-title-main">PER1</span> Protein-coding gene in the species Homo sapiens

The PER1 gene encodes the period circadian protein homolog 1 protein in humans.

In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.

Joseph S. Takahashi is a Japanese American neurobiologist and geneticist. Takahashi is a professor at University of Texas Southwestern Medical Center as well as an investigator at the Howard Hughes Medical Institute. Takahashi's research group discovered the genetic basis for the mammalian circadian clock in 1994 and identified the Clock gene in 1997. Takahashi was elected to the National Academy of Sciences in 2003.

<i>Cycle</i> (gene)

Cycle (cyc) is a gene in Drosophila melanogaster that encodes the CYCLE protein (CYC). The Cycle gene (cyc) is expressed in a variety of cell types in a circadian manner. It is involved in controlling both the sleep-wake cycle and circadian regulation of gene expression by promoting transcription in a negative feedback mechanism. The cyc gene is located on the left arm of chromosome 3 and codes for a transcription factor containing a basic helix-loop-helix (bHLH) domain and a PAS domain. The 2.17 kb cyc gene is divided into 5 coding exons totaling 1,625 base pairs which code for 413 aminos acid residues. Currently 19 alleles are known for cyc. Orthologs performing the same function in other species include ARNTL and ARNTL2.

Doubletime (dbt) also known as discs overgrown (dco) is a gene that encodes the double-time protein (DBT) in Drosophila melanogaster. The double-time protein is a kinase that phosphorylates PER protein that regulates the molecularly-driven, biological clock controlling circadian rhythm. The mammalian homolog of doubletime is casein kinase I epsilon. Different mutations in the dbt gene have been shown to cause lengthening, shortening, or complete loss in period of locomotor activity in flies. Drosophila and certain vertebrate Casein Kinase Id shows circadian function that has been evolutionary conserved over long time spans.

<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".

<span class="mw-page-title-main">Michael W. Young</span> American biologist and geneticist (born 1949)

Michael Warren Young is an American biologist and geneticist. He has dedicated over three decades to research studying genetically controlled patterns of sleep and wakefulness within Drosophila melanogaster.

<span class="mw-page-title-main">Casein kinase 1 isoform epsilon</span> Protein and coding gene in humans

Casein kinase I isoform epsilon or CK1ε, is an enzyme that is encoded by the CSNK1E gene in humans. It is the mammalian homolog of doubletime. CK1ε is a serine/threonine protein kinase and is very highly conserved; therefore, this kinase is very similar to other members of the casein kinase 1 family, of which there are seven mammalian isoforms. CK1ε is most similar to CK1δ in structure and function as the two enzymes maintain a high sequence similarity on their regulatory C-terminal and catalytic domains. This gene is a major component of the mammalian oscillator which controls cellular circadian rhythms. CK1ε has also been implicated in modulating various human health issues such as cancer, neurodegenerative diseases, and diabetes.

Amita Sehgal is a molecular biologist and chronobiologist in the Department of Neuroscience at the Perelman School of Medicine at the University of Pennsylvania. Sehgal was involved in the discovery of Drosophila TIM and many other important components of the Drosophila clock mechanism. Sehgal also played a pivotal role in the development of Drosophila as a model for the study of sleep. Her research continues to be focused on understanding the genetic basis of sleep and also how circadian systems relate to other aspects of physiology.

Paul Hardin is a prominent scientist in the field of chronobiology and a pioneering researcher in the understanding of circadian clocks in flies and mammals. Hardin currently serves as a distinguished professor in the biology department at Texas A&M University. He is best known for his discovery of circadian oscillations in the mRNA of the clock gene Period (per), the importance of the E-Box in per activation, the interlocked feedback loops that control rhythms in activator gene transcription, and the circadian regulation of olfaction in Drosophila melanogaster. Born in a suburb of Chicago, Matteson, Illinois, Hardin currently resides in College Station, Texas, with his wife and three children.

<i>Drosophila</i> circadian rhythm

Drosophila circadian rhythm is a daily 24-hour cycle of rest and activity in the fruit flies of the genus Drosophila. The biological process was discovered and is best understood in the species Drosophila melanogaster. Other than normal sleep-wake activity, D. melanogaster has two unique daily behaviours, namely regular vibration during the process of hatching from the pupa, and during mating. Locomotor activity is maximum at dawn and dusk, while eclosion is at dawn.

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.

dClock (clk) is a gene located on the 3L chromosome of Drosophila melanogaster. Mapping and cloning of the gene indicates that it is the Drosophila homolog of the mouse gene CLOCK (mClock). The Jrk mutation disrupts the transcription cycling of per and tim and manifests dominant effects.

Ravi Allada is an Indian-American chronobiologist studying the circadian and homeostatic regulation of sleep primarily in the fruit fly Drosophila. He is the Edward C. Stuntz Distinguished Professor of Neuroscience and Chair of the Department of Neurobiology at Northwestern University. Working with Michael Rosbash, he positionally cloned the Drosophila Clock gene. In his laboratory at Northwestern, he discovered a conserved mechanism for circadian control of sleep-wake cycle, as well as circuit mechanisms that manage levels of sleep.

References

  1. ↑ Price, Jeffrey L. E-mail interview. 6 April 2017.
  2. ↑ "Faculty Detail: Jeffrey Price, Associate Professor, MBB | Ph.D. Doctoral Faculty." School of Biological Sciences: University of Missouri-Kansas City. Curators of the University of Missouri, n.d. Web. 11 Apr. 2017. Archived 2015-03-16 at the Wayback Machine
  3. ↑ Dunlap, JC (1999). "Molecular bases for circadian clocks". Cell. 96 (2): 271–290. doi: 10.1016/S0092-8674(00)80566-8 . PMID   9988221.
  4. ↑ Sehgal A, Price JL, Man B, Young MW (1994). "Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless". Science. 263 (5153): 1603–06. Bibcode:1994Sci...263.1603S. doi:10.1126/science.8128246. PMID   8128246.
  5. ↑ Vosshal LB, Price JL, Sehgal A, Saez L, Young MW (1994). "Block in nuclear localization of period protein by a second clock mutation, timeless". Science. 263 (5153): 1606–09. Bibcode:1994Sci...263.1606V. doi:10.1126/science.8128247. PMID   8128247.
  6. ↑ Rothenfluh A, Abodeely M, Price JL, Young MW (2000). "Isolation and analysis of six timeless alleles which cause short- or long-period circadian rhythms in Drosophila". Genetics. 156 (2): 665–75. doi:10.1093/genetics/156.2.665. PMC   1461293 . PMID   11014814.
  7. ↑ Price JL, Blau J, Rothenfluh A, Abodeely M, Kloss B, Young MW (1998). "double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation". Cell. 94 (1): 83–95. doi: 10.1016/S0092-8674(00)81224-6 . PMID   9674430.
  8. ↑ Kloss B, Price JL, Saez L, Blau J, Rothenfluh A, Wesley CS, Young MW (1998). "The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iε". Cell. 94 (1): 97–107. doi: 10.1016/S0092-8674(00)81225-8 . PMID   9674431.
  9. ↑ Fan JY, Preuss F, Muskus MJ, Bjes ES, Price JL (2009). "Drosophila and vertebrate casein kinase 1δ exhibits evolutionary conservation of circadian function". Genetics. 181 (1): 139–152. doi:10.1534/genetics.108.094805. PMC   2621163 . PMID   18957703.
  10. 1 2 3 Fan, Jin-Yuan; Agyekum, Boadi; Venkatesan, Anandakrishnan; Hall, David R.; Keightley, Andrew; Bjes, Edward S.; Bouyain, Samuel; Price, Jeffrey L. (2013-11-20). "Noncanonical FK506-Binding Protein BDBT Binds DBT to Enhance Its Circadian Function and Forms Foci at Night". Neuron. 80 (4): 984–996. doi:10.1016/j.neuron.2013.08.004. ISSN   0896-6273. PMC   3869642 . PMID   24210908.
  11. ↑ Venkatesan, Anandakrishnan; Fan, Jin-Yuan; Nauman, Christopher; Price, Jeffrey L. (2015-08-01). "A Doubletime Nuclear Localization Signal Mediates an Interaction with Bride of Doubletime to Promote Circadian Function". Journal of Biological Rhythms. 30 (4): 302–317. doi:10.1177/0748730415588189. ISSN   1552-4531. PMC   5730409 . PMID   26082158.
  12. 1 2 Means JC, Venkatesan A, Gerdes B, Fan JY, Bjes ES, Price JL (2015). "Drosophila Spaghetti and Doubletime Link the Circadian Clock and Light to Caspases, Apoptosis and Tauopathy". PLOS Genetics. 11 (5): e1005171. doi:10.1371/journal.pgen.1005171. PMC   4423883 . PMID   25951229.
  13. ↑ Fan JY, Means JC, Bjes ES, Price JL (2015). "Drosophila DBT autophosphorylation of its C-terminal domain antagonized by SPAG and involved in UV-induced apoptosis". Mol. Cell. Biol. 35 (14): 2414–2424. doi:10.1128/MCB.00390-15. PMC   4475922 . PMID   25939385.
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