Open main menu
Home
Random
Recent changes
Special pages
Community portal
Preferences
About Wikipedia
Disclaimers
Incubator escapee wiki
Search
User menu
Talk
Dark mode
Contributions
Create account
Log in
Editing
Cell cycle
(section)
Warning:
You are not logged in. Your IP address will be publicly visible if you make any edits. If you
log in
or
create an account
, your edits will be attributed to your username, along with other benefits.
Anti-spam check. Do
not
fill this in!
=={{anchor|Regulation_of_cell_cycle}}Regulation of eukaryotic cell cycle== [[File:A simplified view of the cell-cycle control system.pdf|thumb|upright=2|Levels of the three major cyclin types oscillate during the cell cycle (top), providing the basis for oscillations in the cyclin–Cdk complexes that drive cell-cycle events (bottom). Cdk levels are constant and in large excess over cyclin levels; thus, cyclin–Cdk complexes form in parallel with cyclin levels. The enzymatic activities of cyclin–Cdk complexes also tend to rise and fall in parallel with cyclin levels.{{efn|Although in some cases Cdk inhibitor proteins or phosphorylation introduce a delay between the formation and activation of cyclin–Cdk complexes}} Formation of active G1/S–Cdk complexes commits the cell to a new division cycle at the Start checkpoint in late G1. G1/S–Cdks then activate the S–Cdk complexes that initiate DNA replication at the beginning of S phase. M–Cdk activation occurs after the completion of S phase, resulting in progression through the G2/M checkpoint and assembly of the mitotic spindle. APC activation then triggers sister-chromatid separation at the metaphase-to-anaphase transition.{{efn|APC activity also causes the destruction of S and M cyclins and thus the inactivation of Cdks, which promotes the completion of mitosis and cytokinesis.}} APC activity is maintained in G1 until G1/S–Cdk activity rises again and commits the cell to the next cycle.{{efn|This scheme does not apply to all cell types.}}]] Regulation of the cell cycle involves processes crucial to the survival of a cell, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division. The molecular events that control the cell cycle are ordered and directional; that is, each process occurs in a sequential fashion and it is impossible to "reverse" the cycle. ===Role of cyclins and CDKs=== {| class=wikitable align=right |- align=center |[[File:Paul Nurse portrait.jpg|120px]]<br />Nobel Laureate<br />[[Paul Nurse]] |[[File:Tim hunt.jpg|132px]]<br />Nobel Laureate<br />[[Tim Hunt]] |} Two key classes of regulatory molecules, [[cyclin]]s and [[cyclin-dependent kinase]]s (CDKs), determine a cell's progress through the cell cycle.<ref name="pmid7575488">{{cite journal | vauthors = Nigg EA | title = Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle | journal = BioEssays | volume = 17 | issue = 6 | pages = 471–480 | date = June 1995 | pmid = 7575488 | doi = 10.1002/bies.950170603 | s2cid = 44307473 }}</ref> [[Leland H. Hartwell]], [[R. Timothy Hunt]], and [[Paul M. Nurse]] won the 2001 [[Nobel Prize in Physiology or Medicine]] for their discovery of these central molecules.<ref>{{cite web| url=http://nobelprize.org/nobel_prizes/medicine/laureates/2001/press.html | publisher=Nobelprize.org | title=The Nobel Prize in Physiology or Medicine 2001 – Press release}}</ref> Many of the genes encoding cyclins and CDKs are [[conservation (genetics)|conserved]] among all eukaryotes, but in general, more complex organisms have more elaborate cell cycle control systems that incorporate more individual components. Many of the relevant genes were first identified by studying yeast, especially ''[[Saccharomyces cerevisiae]]'';<ref name="pmid9843569">{{cite journal | vauthors = Spellman PT, Sherlock G, Zhang MQ, Iyer VR, Anders K, Eisen MB, Brown PO, Botstein D, Futcher B | display-authors = 6 | title = Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization | journal = Molecular Biology of the Cell | volume = 9 | issue = 12 | pages = 3273–3297 | date = December 1998 | pmid = 9843569 | pmc = 25624 | doi = 10.1091/mbc.9.12.3273 }}</ref> genetic nomenclature in yeast dubs many of these genes ''cdc'' (for "cell division cycle") followed by an identifying number, e.g. ''[[cdc25]]'' or ''[[cdc20]]''. Cyclins form the regulatory subunits and CDKs the catalytic subunits of an activated [[heterodimer]]; cyclins have no catalytic activity and CDKs are inactive in the absence of a partner cyclin. When activated by a bound cyclin, CDKs perform a common biochemical reaction called [[phosphorylation]] that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle. Different cyclin-CDK combinations determine the downstream proteins targeted. CDKs are constitutively expressed in cells whereas cyclins are synthesised at specific stages of the cell cycle, in response to various molecular signals.<ref name="Robbins">{{cite book | vauthors = Robbins SL, Cotran RS | veditors = Kumar V, Abbas AK, Fausto N | title = Pathological Basis of Disease | publisher = [[Elsevier]] |year=2004 |isbn=978-81-8147-528-2}}</ref> ====General mechanism of cyclin-CDK interaction==== Upon receiving a pro-mitotic extracellular signal, G<sub>1</sub> [[cyclin-CDK]] complexes become active to prepare the cell for S phase, promoting the expression of [[transcription factor]]s that in turn promote the expression of S cyclins and of enzymes required for [[DNA replication]]. The G<sub>1</sub> cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for [[ubiquitination]]. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the [[proteasome]]. Results from a study of E2F transcriptional dynamics at the single-cell level argue that the role of G1 cyclin-CDK activities, in particular cyclin D-CDK4/6, is to tune the timing rather than the commitment of cell cycle entry.<ref name="Dong, P. 2014">{{cite journal | vauthors = Dong P, Maddali MV, Srimani JK, Thélot F, Nevins JR, Mathey-Prevot B, You L | title = Division of labour between Myc and G1 cyclins in cell cycle commitment and pace control | journal = Nature Communications | volume = 5 | pages = 4750 | date = September 2014 | pmid = 25175461 | pmc = 4164785 | doi = 10.1038/ncomms5750 | bibcode = 2014NatCo...5.4750D }}</ref> Active S cyclin-CDK complexes phosphorylate proteins that make up the [[pre-replication complex]]es assembled during G<sub>1</sub> phase on DNA [[origin of replication|replication origins]]. The phosphorylation serves two purposes: to activate each already-assembled pre-replication complex, and to prevent new complexes from forming. This ensures that every portion of the cell's [[genome]] will be replicated once and only once. The reason for prevention of gaps in replication is fairly clear, because daughter cells that are missing all or part of crucial genes will die. However, for reasons related to [[gene copy number]] effects, possession of extra copies of certain genes is also deleterious to the daughter cells. Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G<sub>2</sub> phases, promote the initiation of [[mitosis]] by stimulating downstream proteins involved in chromosome condensation and [[mitotic spindle]] assembly. A critical complex activated during this process is a [[ubiquitin ligase]] known as the [[anaphase-promoting complex]] (APC), which promotes degradation of structural proteins associated with the chromosomal [[kinetochore]]. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed.<ref>{{cite journal | vauthors = Mahmoudi M, Azadmanesh K, Shokrgozar MA, Journeay WS, Laurent S | title = Effect of nanoparticles on the cell life cycle | journal = Chemical Reviews | volume = 111 | issue = 5 | pages = 3407–3432 | date = May 2011 | pmid = 21401073 | doi = 10.1021/cr1003166 }}</ref> ====Specific action of cyclin-CDK complexes==== [[Cyclin D]] is the first cyclin produced in the cells that enter the cell cycle, in response to extracellular signals (e.g. [[growth factor]]s). Cyclin D levels stay low in resting cells that are not proliferating. Additionally, [[Cyclin-dependent kinase 4|CDK4/6]] and [[Cyclin-dependent kinase 2|CDK2]] are also inactive because CDK4/6 are bound by [[INK4]] family members (e.g., p16), limiting kinase activity. Meanwhile, CDK2 complexes are inhibited by the CIP/KIP proteins such as p21 and p27,<ref>{{cite journal | vauthors = Goel S, DeCristo MJ, McAllister SS, Zhao JJ | title = CDK4/6 Inhibition in Cancer: Beyond Cell Cycle Arrest | journal = Trends in Cell Biology | volume = 28 | issue = 11 | pages = 911–925 | date = November 2018 | pmid = 30061045 | pmc = 6689321 | doi = 10.1016/j.tcb.2018.07.002 }}</ref> When it is time for a cell to enter the cell cycle, which is triggered by a mitogenic stimuli, levels of cyclin D increase. In response to this trigger, cyclin D binds to existing [[Cyclin-dependent kinase 4|CDK4]]/6, forming the active cyclin D-CDK4/6 complex. Cyclin D-CDK4/6 complexes in turn mono-phosphorylates the [[retinoblastoma]] susceptibility protein ([[Retinoblastoma protein|Rb]]) to pRb. The un-phosphorylated Rb tumour suppressor functions in inducing cell cycle exit and maintaining G0 arrest (senescence).<ref>{{cite journal | vauthors = Burkhart DL, Sage J | title = Cellular mechanisms of tumour suppression by the retinoblastoma gene | journal = Nature Reviews. Cancer | volume = 8 | issue = 9 | pages = 671–682 | date = September 2008 | pmid = 18650841 | pmc = 6996492 | doi = 10.1038/nrc2399 }}</ref> In the last few decades, a model has been widely accepted whereby pRB proteins are inactivated by cyclin D-Cdk4/6-mediated phosphorylation. Rb has 14+ potential phosphorylation sites. Cyclin D-Cdk 4/6 progressively phosphorylates Rb to hyperphosphorylated state, which triggers dissociation of pRB–[[E2F]] complexes, thereby inducing G1/S cell cycle gene expression and progression into S phase.<ref>{{cite book | vauthors = Morgan DO |title=The cell cycle : principles of control |date=2007 |publisher=New Science Press |isbn=978-0-19-920610-0 |location=London |oclc=70173205 }}</ref> Scientific observations from a study have shown that Rb is present in three types of isoforms: (1) un-phosphorylated Rb in G0 state; (2) mono-phosphorylated Rb, also referred to as "hypo-phosphorylated' or 'partially' phosphorylated Rb in early G1 state; and (3) inactive hyper-phosphorylated Rb in late G1 state.<ref>{{cite journal | vauthors = Paternot S, Bockstaele L, Bisteau X, Kooken H, Coulonval K, Roger PP | title = Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase | journal = Cell Cycle | volume = 9 | issue = 4 | pages = 689–699 | date = February 2010 | pmid = 20107323 | doi = 10.4161/cc.9.4.10611 | doi-access = free | url = https://dipot.ulb.ac.be/dspace/bitstream/2013/57637/1/17-PaternotCC9-4.pdf }}</ref><ref>{{cite journal | vauthors = Henley SA, Dick FA | title = The retinoblastoma family of proteins and their regulatory functions in the mammalian cell division cycle | journal = Cell Division | volume = 7 | issue = 1 | pages = 10 | date = March 2012 | pmid = 22417103 | pmc = 3325851 | doi = 10.1186/1747-1028-7-10 | doi-access = free }}</ref><ref name=":0">{{cite journal | vauthors = Narasimha AM, Kaulich M, Shapiro GS, Choi YJ, Sicinski P, Dowdy SF | title = Cyclin D activates the Rb tumor suppressor by mono-phosphorylation | journal = eLife | volume = 3 | pages = e02872 | date = June 2014 | pmid = 24876129 | pmc = 4076869 | doi = 10.7554/eLife.02872 | doi-access = free }}</ref> In early G1 cells, mono-phosphorylated Rb exists as 14 different isoforms, one of each has distinct [[E2F]] binding affinity.<ref name=":0" /> Rb has been found to associate with hundreds of different proteins<ref>{{cite book | vauthors = Morris EJ, Dyson NJ | title = Retinoblastoma protein partners | volume = 82 | pages = [https://archive.org/details/advancesincancer0000unse_w5o8/page/1 1–54] | date = 2001-01-01 | pmid = 11447760 | doi = 10.1016/s0065-230x(01)82001-7 | publisher = Academic Press | isbn = 9780120066827 | series = Advances in Cancer Research | url = https://archive.org/details/advancesincancer0000unse_w5o8/page/1 }}</ref> and the idea that different mono-phosphorylated Rb isoforms have different protein partners was very appealing.<ref name="pmid27401552">{{cite journal | vauthors = Dyson NJ | title = RB1: a prototype tumor suppressor and an enigma | journal = Genes & Development | volume = 30 | issue = 13 | pages = 1492–1502 | date = July 2016 | pmid = 27401552 | pmc = 4949322 | doi = 10.1101/gad.282145.116 }}</ref> A later report confirmed that mono-phosphorylation controls Rb's association with other proteins and generates functional distinct forms of Rb.<ref name="Sanidas">{{cite journal | vauthors = Sanidas I, Morris R, Fella KA, Rumde PH, Boukhali M, Tai EC, Ting DT, Lawrence MS, Haas W, Dyson NJ | display-authors = 6 | title = A Code of Mono-phosphorylation Modulates the Function of RB | journal = Molecular Cell | volume = 73 | issue = 5 | pages = 985–1000.e6 | date = March 2019 | pmid = 30711375 | pmc = 6424368 | doi = 10.1016/j.molcel.2019.01.004 }}</ref> All different mono-phosphorylated Rb isoforms inhibit E2F transcriptional program and are able to arrest cells in G1-phase. Different mono-phosphorylated forms of Rb have distinct transcriptional outputs that are extended beyond E2F regulation.<ref name="Sanidas" /> In general, the binding of pRb to E2F inhibits the E2F target gene expression of certain G1/S and S transition genes including [[Cyclin E|E-type cyclins]]. The partial phosphorylation of Rb de-represses the Rb-mediated suppression of E2F target gene expression, begins the expression of cyclin E. The molecular mechanism that causes the cell switched to cyclin E activation is currently not known, but as cyclin E levels rise, the active cyclin E-CDK2 complex is formed, bringing Rb to be inactivated by hyper-phosphorylation.<ref name=":0" /> Hyperphosphorylated Rb is completely dissociated from E2F, enabling further expression of a wide range of E2F target genes are required for driving cells to proceed into S phase [1]. It has been identified that cyclin D-Cdk4/6 binds to a C-terminal alpha-helix region of Rb that is only distinguishable to cyclin D rather than other cyclins, [[cyclin E]], [[Cyclin A|A]] and [[Cyclin B|B]].<ref name=":1">{{cite journal | vauthors = Topacio BR, Zatulovskiy E, Cristea S, Xie S, Tambo CS, Rubin SM, Sage J, Kõivomägi M, Skotheim JM | display-authors = 6 | title = Cyclin D-Cdk4,6 Drives Cell-Cycle Progression via the Retinoblastoma Protein's C-Terminal Helix | journal = Molecular Cell | volume = 74 | issue = 4 | pages = 758–770.e4 | date = May 2019 | pmid = 30982746 | pmc = 6800134 | doi = 10.1016/j.molcel.2019.03.020 }}</ref> This observation based on the structural analysis of Rb phosphorylation supports that Rb is phosphorylated in a different level through multiple Cyclin-Cdk complexes. This also makes feasible the current model of a simultaneous switch-like inactivation of all mono-phosphorylated Rb isoforms through one type of Rb hyper-phosphorylation mechanism. In addition, mutational analysis of the cyclin D- Cdk 4/6 specific Rb C-terminal helix shows that disruptions of cyclin D-Cdk 4/6 binding to Rb prevents Rb phosphorylation, arrests cells in G1, and bolsters Rb's functions in tumor suppressor.<ref name=":1" /> This cyclin-Cdk driven cell cycle transitional mechanism governs a cell committed to the cell cycle that allows cell proliferation. A cancerous cell growth often accompanies with deregulation of Cyclin D-Cdk 4/6 activity. The hyperphosphorylated Rb dissociates from the E2F/DP1/Rb complex (which was bound to the [[E2F]] responsive genes, effectively "blocking" them from transcription), activating E2F. Activation of E2F results in transcription of various genes like [[cyclin E]], [[cyclin A]], [[DNA polymerase]], [[thymidine kinase]], etc. Cyclin E thus produced binds to [[Cyclin-dependent kinase 2|CDK2]], forming the cyclin E-CDK2 complex, which pushes the cell from G<sub>1</sub> to S phase (G<sub>1</sub>/S, which initiates the G<sub>2</sub>/M transition).<ref name="isbn0-12-324719-5">{{cite book | vauthors = Norbury C | veditors = Hardie DG, Hanks S | title = Protein kinase factsBook | publisher = Academic Press | location = Boston | year = 1995 | pages = [https://archive.org/details/proteinkinasefac0000unse/page/184 184] | chapter = Cdk2 protein kinase (vertebrates) | isbn = 978-0-12-324719-3 | chapter-url = https://archive.org/details/proteinkinasefac0000unse/page/184 }}</ref> [[Cyclin B]]-cdk1 complex activation causes breakdown of [[nuclear envelope]] and initiation of [[prophase]], and subsequently, its deactivation causes the cell to exit mitosis.<ref name="Robbins" /> A quantitative study of E2F transcriptional dynamics at the single-cell level by using engineered fluorescent reporter cells provided a quantitative framework for understanding the control logic of cell cycle entry, challenging the canonical textbook model. Genes that regulate the amplitude of E2F accumulation, such as Myc, determine the commitment in cell cycle and S phase entry. G1 cyclin-CDK activities are not the driver of cell cycle entry. Instead, they primarily tune the timing of E2F increase, thereby modulating the pace of cell cycle progression.<ref name="Dong, P. 2014" /> === Inhibitors === ==== Endogenous ==== [[Image:Signal transduction pathways.svg|500px|thumb|Overview of signal transduction pathways involved in [[apoptosis]], also known as "programmed cell death"]] Two families of genes, the ''cip/kip'' (''CDK interacting protein/Kinase inhibitory protein'') family and the INK4a/ARF (''In''hibitor of ''K''inase 4/''A''lternative ''R''eading ''F''rame) family, prevent the progression of the cell cycle. Because these genes are instrumental in prevention of [[tumor]] formation, they are known as [[tumor suppressor]]s. The '''''cip/kip'' family''' includes the genes [[p21]], [[p27 (gene)|p27]] and [[P57 (gene)|p57]]. They halt the cell cycle in G<sub>1</sub> phase by binding to and inactivating cyclin-CDK complexes. p21 is activated by [[p53]] (which, in turn, is triggered by DNA damage e.g. due to radiation). p27 is activated by Transforming Growth Factor β ([[TGF β]]), a growth inhibitor. The '''INK4a/ARF family''' includes [[p16 (gene)|p16<sup>INK4a</sup>]], which binds to CDK4 and arrests the cell cycle in G<sub>1</sub> phase, and [[p14arf|p14<sup>ARF</sup>]] which prevents p53 degradation. ==== Synthetic ==== Synthetic inhibitors of [[Cdc25]] could also be useful for the arrest of cell cycle and therefore be useful as antineoplastic and anticancer agents.<ref name="ref 1">{{cite web |url=http://pharmaxchange.info/presentations/cdc25.html |title=Presentation on CDC25 PHOSPHATASES: A Potential Target for Novel Anticancer Agents |access-date=11 March 2010 |archive-url=https://web.archive.org/web/20160303231929/http://pharmaxchange.info/presentations/cdc25.html |archive-date=3 March 2016 |url-status=dead}}</ref> Many human cancers possess the hyper-activated Cdk 4/6 activities.<ref>{{cite journal | vauthors = Sherr CJ, Beach D, Shapiro GI | title = Targeting CDK4 and CDK6: From Discovery to Therapy | journal = Cancer Discovery | volume = 6 | issue = 4 | pages = 353–367 | date = April 2016 | pmid = 26658964 | pmc = 4821753 | doi = 10.1158/2159-8290.cd-15-0894 }}</ref> Given the observations of cyclin D-Cdk 4/6 functions, inhibition of Cdk 4/6 should result in preventing a malignant tumor from proliferating. Consequently, scientists have tried to invent the synthetic Cdk4/6 inhibitor as Cdk4/6 has been characterized to be a therapeutic target for anti-tumor effectiveness. Three Cdk4/6 inhibitors – [[palbociclib]], [[ribociclib]], and [[abemaciclib]] – currently received FDA approval for clinical use to treat advanced-stage or [[Metastatic breast cancer|metastatic]], [[Hormone receptor positive breast tumor|hormone-receptor-positive]] (HR-positive, HR+), [[HER2 negative breast cancer|HER2-negative]] (HER2-) breast cancer.<ref>{{cite journal | vauthors = O'Leary B, Finn RS, Turner NC | title = Treating cancer with selective CDK4/6 inhibitors | journal = Nature Reviews. Clinical Oncology | volume = 13 | issue = 7 | pages = 417–430 | date = July 2016 | pmid = 27030077 | doi = 10.1038/nrclinonc.2016.26 | s2cid = 23646632 }}</ref><ref name="Bilgin_2017">{{cite journal | vauthors = Bilgin B, Sendur MA, Şener Dede D, Akıncı MB, Yalçın B | title = A current and comprehensive review of cyclin-dependent kinase inhibitors for the treatment of metastatic breast cancer | journal = Current Medical Research and Opinion | volume = 33 | issue = 9 | pages = 1559–1569 | date = September 2017 | pmid = 28657360 | doi = 10.1080/03007995.2017.1348344 | s2cid = 205542255 }}</ref> For example, palbociclib is an orally active CDK4/6 inhibitor which has demonstrated improved outcomes for ER-positive/HER2-negative advanced breast cancer. The main side effect is [[neutropenia]] which can be managed by dose reduction.<ref name="Schmidt_2018">{{cite book | vauthors = Schmidt M, Sebastian M | title = Small Molecules in Oncology | chapter = Palbociclib—The First of a New Class of Cell Cycle Inhibitors | series = Recent Results in Cancer Research | volume = 211 | pages = 153–175 | date = August 2018 | pmid = 30069766 | doi = 10.1007/978-3-319-91442-8_11 | isbn = 978-3-319-91441-1 }}</ref> Cdk4/6 targeted therapy will only treat cancer types where Rb is expressed. Cancer cells with loss of Rb have primary resistance to Cdk4/6 inhibitors. ===Transcriptional regulatory network=== Current evidence suggests that a semi-autonomous transcriptional network acts in concert with the CDK-cyclin machinery to regulate the cell cycle. Several gene expression studies in ''[[Saccharomyces cerevisiae]]'' have identified 800–1200 genes that change expression over the course of the cell cycle.<ref name="pmid9843569" /><ref name="pramilaetal2006">{{cite journal | vauthors = Pramila T, Wu W, Miles S, Noble WS, Breeden LL | title = The Forkhead transcription factor Hcm1 regulates chromosome segregation genes and fills the S-phase gap in the transcriptional circuitry of the cell cycle | journal = Genes & Development | volume = 20 | issue = 16 | pages = 2266–2278 | date = August 2006 | pmid = 16912276 | pmc = 1553209 | doi = 10.1101/gad.1450606 }}</ref><ref name="orlandoeta1nature2008">{{cite journal | vauthors = Orlando DA, Lin CY, Bernard A, Wang JY, Socolar JE, Iversen ES, Hartemink AJ, Haase SB | display-authors = 6 | title = Global control of cell-cycle transcription by coupled CDK and network oscillators | journal = Nature | volume = 453 | issue = 7197 | pages = 944–947 | date = June 2008 | pmid = 18463633 | pmc = 2736871 | doi = 10.1038/nature06955 | bibcode = 2008Natur.453..944O }}</ref> They are transcribed at high levels at specific points in the cell cycle, and remain at lower levels throughout the rest of the cycle. While the set of identified genes differs between studies due to the computational methods and criteria used to identify them, each study indicates that a large portion of yeast genes are temporally regulated.<ref name="deLichtenberg2005">{{cite journal | vauthors = de Lichtenberg U, Jensen LJ, Fausbøll A, Jensen TS, Bork P, Brunak S | title = Comparison of computational methods for the identification of cell cycle-regulated genes | journal = Bioinformatics | volume = 21 | issue = 7 | pages = 1164–1171 | date = April 2005 | pmid = 15513999 | doi = 10.1093/bioinformatics/bti093 | doi-access = free }}</ref> Many periodically expressed genes are driven by [[transcription factor]]s that are also periodically expressed. One screen of single-gene knockouts identified 48 transcription factors (about 20% of all non-essential transcription factors) that show cell cycle progression defects.<ref name="whiteetal2009">{{cite journal | vauthors = White MA, Riles L, Cohen BA | title = A systematic screen for transcriptional regulators of the yeast cell cycle | journal = Genetics | volume = 181 | issue = 2 | pages = 435–446 | date = February 2009 | pmid = 19033152 | pmc = 2644938 | doi = 10.1534/genetics.108.098145 }}</ref> Genome-wide studies using high throughput technologies have identified the transcription factors that bind to the promoters of yeast genes, and correlating these findings with temporal expression patterns have allowed the identification of transcription factors that drive phase-specific gene expression.<ref name="pramilaetal2006" /><ref name="leeetal2002">{{cite journal | vauthors = Lee TI, Rinaldi NJ, Robert F, Odom DT, Bar-Joseph Z, Gerber GK, Hannett NM, Harbison CT, Thompson CM, Simon I, Zeitlinger J, Jennings EG, Murray HL, Gordon DB, Ren B, Wyrick JJ, Tagne JB, Volkert TL, Fraenkel E, Gifford DK, Young RA | display-authors = 6 | title = Transcriptional regulatory networks in Saccharomyces cerevisiae | journal = Science | volume = 298 | issue = 5594 | pages = 799–804 | date = October 2002 | pmid = 12399584 | doi = 10.1126/science.1075090 | s2cid = 4841222 | bibcode = 2002Sci...298..799L }}</ref> The expression profiles of these transcription factors are driven by the transcription factors that peak in the prior phase, and computational models have shown that a CDK-autonomous network of these transcription factors is sufficient to produce steady-state oscillations in gene expression).<ref name="orlandoeta1nature2008" /><ref name="simonetal2001">{{cite journal | vauthors = Simon I, Barnett J, Hannett N, Harbison CT, Rinaldi NJ, Volkert TL, Wyrick JJ, Zeitlinger J, Gifford DK, Jaakkola TS, Young RA | display-authors = 6 | title = Serial regulation of transcriptional regulators in the yeast cell cycle | journal = Cell | volume = 106 | issue = 6 | pages = 697–708 | date = September 2001 | pmid = 11572776 | doi = 10.1016/S0092-8674(01)00494-9 | s2cid = 9308235 | doi-access = free }}</ref> Experimental evidence also suggests that gene expression can oscillate with the period seen in dividing wild-type cells independently of the CDK machinery. Orlando ''et al.'' used [[microarray]]s to measure the expression of a set of 1,271 genes that they identified as periodic in both wild type cells and cells lacking all S-phase and mitotic cyclins (''clb1,2,3,4,5,6''). Of the 1,271 genes assayed, 882 continued to be expressed in the cyclin-deficient cells at the same time as in the wild type cells, despite the fact that the cyclin-deficient cells arrest at the border between [[G1 phase|G<sub>1</sub>]] and [[S phase]]. However, 833 of the genes assayed changed behavior between the wild type and mutant cells, indicating that these genes are likely directly or indirectly regulated by the CDK-cyclin machinery. Some genes that continued to be expressed on time in the mutant cells were also expressed at different levels in the mutant and wild type cells. These findings suggest that while the transcriptional network may oscillate independently of the CDK-cyclin oscillator, they are coupled in a manner that requires both to ensure the proper timing of cell cycle events.<ref name="orlandoeta1nature2008" /> Other work indicates that [[phosphorylation]], a post-translational modification, of cell cycle transcription factors by [[Cdk1]] may alter the localization or activity of the transcription factors in order to tightly control timing of target genes.<ref name="whiteetal2009" /><ref name="sidorova1995">{{cite journal | vauthors = Sidorova JM, Mikesell GE, Breeden LL | title = Cell cycle-regulated phosphorylation of Swi6 controls its nuclear localization | journal = Molecular Biology of the Cell | volume = 6 | issue = 12 | pages = 1641–1658 | date = December 1995 | pmid = 8590795 | pmc = 301322 | doi = 10.1091/mbc.6.12.1641 }}</ref><ref name="ubersaxetal2003">{{cite journal | vauthors = Ubersax JA, Woodbury EL, Quang PN, Paraz M, Blethrow JD, Shah K, Shokat KM, Morgan DO | display-authors = 6 | title = Targets of the cyclin-dependent kinase Cdk1 | journal = Nature | volume = 425 | issue = 6960 | pages = 859–864 | date = October 2003 | pmid = 14574415 | doi = 10.1038/nature02062 | s2cid = 4391711 | bibcode = 2003Natur.425..859U }}</ref> While oscillatory transcription plays a key role in the progression of the yeast cell cycle, the CDK-cyclin machinery operates independently in the early embryonic cell cycle. Before the [[midblastula transition]], [[zygote|zygotic]] transcription does not occur and all needed proteins, such as the B-type cyclins, are translated from maternally loaded [[mRNA]].<ref name="davidmorganbook2007">{{cite book | vauthors = Morgan DO | title = The Cell Cycle: Principles of Control | publisher = New Science Press | location = London | year = 2007 | pages = 18 | chapter = 2–3 | isbn = 978-0-9539181-2-6 }}</ref> ===DNA replication and DNA replication origin activity=== Analyses of synchronized cultures of ''Saccharomyces cerevisiae'' under conditions that prevent DNA replication initiation without delaying cell cycle progression showed that origin licensing decreases the expression of genes with origins near their 3' ends, revealing that downstream origins can regulate the expression of upstream genes.<ref>{{cite journal | vauthors = Omberg L, Meyerson JR, Kobayashi K, Drury LS, Diffley JF, Alter O | title = Global effects of DNA replication and DNA replication origin activity on eukaryotic gene expression | journal = Molecular Systems Biology | volume = 5 | pages = 312 | date = October 2009 | pmid = 19888207 | pmc = 2779084 | doi = 10.1038/msb.2009.70 }}</ref> This confirms previous predictions from mathematical modeling of a global causal coordination between DNA replication origin activity and mRNA expression,<ref>{{cite conference | vauthors = Alter O, Golub GH, Brown PO, Botstein D | title = Novel Genome-Scale Correlation between DNA Replication and RNA Transcription During the Cell Cycle in Yeast is Predicted by Data-Driven Models | veditors = Deutscher MP, Black S, Boehmer PE, D'Urso G, Fletcher TM, Huijing F, Marshall A, Pulverer B, Renault B, Rosenblatt JD, Slingerland JM, Whelan WJ | display-editors = 6 | conference = Miami Nature Biotechnology Winter Symposium | series = Cell Cycle, Chromosomes and Cancer | location = Miami Beach, FL | publisher = University of Miami School of Medicine | volume = 15 | date = February 2004 | url = http://www.med.miami.edu/mnbws/documents/Alter-.pdf | access-date = 7 February 2014 | archive-date = 9 September 2014 | archive-url = https://web.archive.org/web/20140909235805/http://www.med.miami.edu/mnbws/documents/Alter-.pdf | url-status = dead }}</ref><ref>{{cite journal | vauthors = Alter O, Golub GH | title = Integrative analysis of genome-scale data by using pseudoinverse projection predicts novel correlation between DNA replication and RNA transcription | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 47 | pages = 16577–16582 | date = November 2004 | pmid = 15545604 | pmc = 534520 | doi = 10.1073/pnas.0406767101 | doi-access = free | bibcode = 2004PNAS..10116577A }}</ref><ref>{{cite journal | vauthors = Omberg L, Golub GH, Alter O | title = A tensor higher-order singular value decomposition for integrative analysis of DNA microarray data from different studies | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 47 | pages = 18371–18376 | date = November 2007 | pmid = 18003902 | pmc = 2147680 | doi = 10.1073/pnas.0709146104 | doi-access = free | bibcode = 2007PNAS..10418371O }}</ref> and shows that mathematical modeling of DNA microarray data can be used to correctly predict previously unknown biological modes of regulation.
Edit summary
(Briefly describe your changes)
By publishing changes, you agree to the
Terms of Use
, and you irrevocably agree to release your contribution under the
CC BY-SA 4.0 License
and the
GFDL
. You agree that a hyperlink or URL is sufficient attribution under the Creative Commons license.
Cancel
Editing help
(opens in new window)