Sic1

Last updated
Sic1
Identifiers
SymbolSic1
Alt. symbolsYLR079W, SDB25, SIC1_YEAST, CDK inhibitor p40
NCBI gene 850768
UniProt P38634

Sic1, a protein, is a stoichiometric inhibitor [1] of Cdk1-Clb (B-type cyclins) complexes in the budding yeast Saccharomyces cerevisiae . Because B-type cyclin-Cdk1 complexes are the drivers of S-phase initiation, Sic1 prevents premature S-phase entry. [2] Multisite phosphorylation of Sic1 is thought to time Sic1 ubiquitination and destruction, and by extension, the timing of S-phase entry. [3]

Contents

Cell cycle control

Fig. 1 The diagram shows the role of Sic1 in Clb5,6-Cdk1 inhibition and its phosphorylation-mediated polyubiquitination and destruction. Destruction allows for Clb5,6-Cdk1 activity and S-phase entry. Sic1 David Morgan10-5.jpg
Fig. 1 The diagram shows the role of Sic1 in Clb5,6-Cdk1 inhibition and its phosphorylation-mediated polyubiquitination and destruction. Destruction allows for Clb5,6-Cdk1 activity and S-phase entry.

In the G1 phase of the cell cycle, Sic1 binds tightly to the Cdc28-Clb complex and inhibits it. [4] Low Cdc28-Clb activity leads to the disassembly of the mitotic spindle, the assembly of the prereplicative complex and initiation of bud formation in yeast.

At the START point in the yeast cell cycle, the G1-cyclins Cln3, Cln1 and Cln 2 activate Cdc28. The activated complex will phosphorylate Sic1 at multiple sites which leads to its degradation by the SCF complex. [5] When Sic1 is degraded, the Cdc28-Clb complex is no longer inhibited and the cell can enter the S/M-phase. Thus Sic1 inactivation is essential for transition into S phase (Fig.1).

Cdc28 in complex with B-type cyclin (Cdc28-Clb) phosphorylates Swi5, the transcription factor of Sic1. This promotes the export of Swi5 from the nucleus to the cytoplasm and avoids further transcription of the cdk inhibitor. Cdc28-Clb also phosphorylates any Sic1 molecules still available and triggers their ubiquitin-dependent degradation, exactly like Cdc28-Cln. [4] High Cdc28-Clb levels also initiate DNA replication and duplication of the spindle pole bodies (SPBs). Then the metaphase spindle assembles and chromosome segregation can occur. The transcription of Sic1 starts during telophase, mediated by Swi5. Aca2 is another transcription factor of Sic1, but remains inactive until G1. [6] At the end of mitosis, Sic1 is involved in the inactivation of Cdc28-Clb. [7]

Ubiquitin-dependent degradation

Fig. 2 The first step of the degradation of Sic1 is its phosphorylation by Cdc28-Cln followed by the degradation through SCF. Sic1 fig2 eng.jpg
Fig. 2 The first step of the degradation of Sic1 is its phosphorylation by Cdc28-Cln followed by the degradation through SCF.

In order to be recognized by Cdc4 of the SCF complex, Sic1 has to be phosphorylated, often by Cyclin-Cdk complexes, at least at 6 of the 9 cdk sites (Fig. 2). [8] Sic1 can also be phosphorylated by other kinases, such as Pho85-Pc11, a kinase which becomes essential when Cln1 and Cln2 are absent. [9] Sic1 has also a role in the response to osmostress. The stress-activated protein kinase (SAPK) Hog1 phosphorylates Sic1 at a single residue at the carboxyl terminus. This leads to downregulation of cyclin expression and Sic1 stabilization which arrests the cell cycle. [10]

Phosphorylation

Sic1 needs to be phosphorylated at multiple sites for ubiquitination-driven degradation (Fig. 2). The multiple phosphorylations are required for Sic1 to be recruited by Cdc4 to the SCF complex. [11] The Cdc4 substrate recognition mechanism includes the interaction with consensus binding motifs on the surface of the folded and phosphorylated Sic1, the so-called Cdc4 phospho-degrons (CPD). It has been shown that the optimal consensus sequence for Cdc4 is a phosphorylated serine or threonine followed by a proline and a basic amino acid. However, none of the CPDs on the surface of the Sic1 show such a composition. Therefore, multiple phosphorylation of Sic1 is necessary to get high-affinity binding to Cdc4. [8] Although this mechanism looks inefficient, it provides advantages for a cell because it is possible to measure the environmental Cln/cdc28 concentration. The number of phosphorylated sites corresponds to the concentration of Cln/cdc28 and Sic1 could be considered as a sensor for this protein. In contrast to the many sharp transitions of ultrasensitive kinase cascade feedback loops, this mechanism allows fine tuned regulation. [8] Moreover, because multiple phosphorylations are required, the probability that Sic1 is degraded by random is small. Using multiple phosphorylation of Sic1, the cell evolved a strategy to highly regulate the onset of DNA replication that is absolutely vital to provide genetic stability.

A simplified understanding of the regulation of Sic1 degradation involves the phosphorylation of multiple CDK sites, which consist of optimal and suboptimal consensus phosphorylation motifs. Recent studies conducted by Koivomagi et al. have revealed the many intricacies of the multi-phosphorylation reaction between the cyclin-CDK complex and the Sic1 protein. These studies unveil the important characteristics of the Sic1 CDK phosphorylation sites, which include priming sites, binding sites, degron pairs, distancing of phosphorylation sites, and relative site location. In addition, the studies also emphasize the influence of other factors on Sic1 phosphorylation, including the Cks1 phospho-binding pocket, cyclin docking motifs, and Cdk1 active site specificity. All of these mechanisms contribute to the dynamics of the sequence of events leading to Sic1 degradation and initiation of S-phase. [12] [13]

Function

Apart from being an often-overlooked component of the Cdk1 cyclin complex, Cks1 is critical for Sic1 multi-phosphorylation and degradation. The phospho-binding pocket of Cks1 is capable of binding independently to phosphorylated CDK sites on Sic1. Additionally, the binding affinity of Cks1 for phosphoserines is extremely weak, essentially making Cks1 binding dependent on the presence of phosphothreonines only. Thus, in Sic1 mutants with one Cdk1 phosphorylation site or only phosphoserines present, Cks1 is unable to properly bind to the substrate and promote Sic1 multi-phosphorylation. This provides a strong argument for a processive phosphorylation mechanism instead of the previous theory of a random distributive phosphorylation model. [8] In addition to requiring threonine, Cks1 binding to Sic1 can be enhanced with the introduction of a proline residue at the -2 position relative to the threonine residue. [12] [13]

Site positioning

Fig. 3 Sic1 protein distinguished by different protein chains. The protein has disordered regions, allowing it to be a useful tool in studying and manipulating phosphorylation sites. Sic1 Protein.png
Fig. 3 Sic1 protein distinguished by different protein chains. The protein has disordered regions, allowing it to be a useful tool in studying and manipulating phosphorylation sites.

Sic1 is a molecule with disordered regions, which aids in the manipulation of phosphorylation site distances. For the following findings, Koivomagi et al. utilized a Sic1 construct with a T33 optimal consensus motif, acting as the primary phosphorylation site, and a suboptimal motif, acting as a secondary site. [12] [13]

When limiting observations to only double-phosphorylated Sic1 constructs, a two-step phosphorylation process was observed, where the first step was primary site phosphorylation. However, the secondary site must be located towards the C-terminus of the protein relative to the primary site for phosphorylation to occur. Secondary site phosphorylation is also sensitive to positioning. Peak phosphorylation rates were found between the +12 to +16 amino acid distances, with a distinct increase around the +10 to +12 range and gradual decrease across the +20 to +30 range. The introduction of the -2 proline residue enhances phosphorylation both in vitro by expanding the peak phosphorylation range, but does not increase phosphorylation activity at distances less than +10. This expansion of the peak phosphorylation range could possibly be attributed to enhanced binding of the priming site to Cks1. [12] [13]

A simple Sic1 construct containing 5 phosphorylation residues (1 priming site and two phosphodegron pairs) revealed that any slight movement of the priming site can have significant effects on cell cycle progression. The priming site should be within the +12 to +16 range of both residues in the phosphodegron pair to maximize phosphorylation. [12] [13]

Directionality

Sic1 phosphorylation is initiated by the G1 cyclins, Cln1,2, and then completed by S-phase cyclins, Clb5,6 (Fig. 1). The docking motifs of the cyclin participate in Sic1 phosphorylation dynamics. S-phase cyclins use RXL docking while G1 cyclins use LLPP docking. Sic1 phosphorylation increases when the RXL motif of Clb5 is +16 to +20 positions relative to the optimal CDK motif. RXL positioning located N-terminal to the motif led to negligible amounts of phosphorylation. In contrast, moving the LLPP motif away from the priming site increases Cln2 phosphorylation, regardless of directionality. [12] [13]

Processivity

Fig. 4 Sic1 Phosphorylation Mechanism 1. In mechanism 1, Koivomagi proposes that the phosphorylated primary site immediately shifts over to another location so that another CDK site can be phosphorylated during the same binding event. Sic1 Phosphorylation Mechanism 1 Clear.pdf
Fig. 4 Sic1 Phosphorylation Mechanism 1. In mechanism 1, Koivomagi proposes that the phosphorylated primary site immediately shifts over to another location so that another CDK site can be phosphorylated during the same binding event.
Fig. 5 Sic1 Phosphorylation Mechanism 2. Koivomagi proposes that phosphorylated primary site does not dissociate from the complex so that the intermediate CDK sites are sequentially phosphorylated in a single binding event. Sic1 Phosphorylation Mechanism 2.pdf
Fig. 5 Sic1 Phosphorylation Mechanism 2. Koivomagi proposes that phosphorylated primary site does not dissociate from the complex so that the intermediate CDK sites are sequentially phosphorylated in a single binding event.

Cks1-dependent multi-phosphorylation occurs in a processive or semi-processive manner, evidenced by the lack of intermediate Sic1 phosphorylation states in normal cells. This processivity is also dependent on the presence of the cyclin docking site since increasing the numbers of mutations in this site decreases the net phosphorylation rate. Processive phosphorylation has two plausible mechanisms where a single binding event leads to the phosphorylation of two or more sites. The first mechanism proposes that, without dissociating from the enzyme complex, the primary site is phosphorylated and immediately shifted from the active site to the Cks1 binding pocket to allow for the additional phosphorylation of other CDK sites. The second mechanism proposes that the phosphorylated primary site binds to another location and is continuously bound while other CDK sites bind to the active site in a sequential manner for multi-phosphorylation. Simulations predict that the probability of a second phosphorylation event after the first, without dissociation, is 40% and 20-40% for the first and second mechanism, respectively. [12] [13]

Sic1 is targeted for degradation by SCF (Cdc4), which recognizes Sic1 phosphodegron pairs. These phosphodegron pairs are closely positioned paired phosphorylation residues that each have strong affinities for Cdc4. In a Sic1 construct with the S69/S76/S80 cluster, processive phosphorylation of these phosphodegron pairs are reliant on Cdk1 sites. Clb5 processivity is dependent on the T5 and T33 sites, while Cln2 processivity is dependent on T5. Reintroduction of various residues led to the discovery of the T33 residue serving as a docking site for the T45/T48 phosphodegron pair, which is able to promote Sic1 degradation to a certain extent in the absence of other phosphodegron pairs. [12] [13]

Mechanism

The following is a proposed mechanism by Koivomagi et al. of the in vivo cascade to promote Sic1 phosphorylation and degradation.

In late G1, Sic1 is inhibiting the Clb5-Cdk1 complex, simultaneously inhibiting its own degradation. The phosphorylation cascade proceeds by Cln2-Cdk1 phosphorylation of the T5 priming site. Following this, the T33, T45, and S76 residues are phosphorylated by Cln2-Cdk1, but no degron pairs are phosphorylated. However, these phosphorylated sites enhance Clb5-Cdk1 docking, leading to increased Sic1 phosphorylation at suboptimal sites and a positive feedback loop where Clb5-Cdk1 inhibition is continually decreased while Sic1 degradation is increased. [12] [13]

Sic1 homologue in human and diseases

The protein p27Kip1 is a human homologue of Sic1, both having a conserved inhibitory domain, [14] but p27Kip1 inhibits G1 cyclins and not cyclin B.

There are several human diseases that are linked to p27Kip1 and other cyclin kinase inhibitors:

Thus, the human Cdk inhibitor p27Kip1 is a potential tumor suppressor protein. If its expression is reduced, the result might be unregulated progression from G1 to S-phase which deregulates cell division and simplifies the formation of tumors.

See also

Related Research Articles

Anaphase-promoting complex

Anaphase-promoting complex is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin (Apc2) and RING (Apc11) subunit much like SCF. Other parts of the APC/C still have unknown functions, but are highly conserved.

Cyclin-dependent kinase

Cyclin-dependent kinases (CDKs) are the families of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved. In fact, yeast cells can proliferate normally when their CDK gene has been replaced with the homologous human gene. CDKs are relatively small proteins, with molecular weights ranging from 34 to 40 kDa, and contain little more than the kinase domain. By definition, a CDK binds a regulatory protein called a cyclin. Without cyclin, CDK has little kinase activity; only the cyclin-CDK complex is an active kinase but its activity can be typically further modulated by phosphorylation and other binding proteins, like p27. CDKs phosphorylate their substrates on serines and threonines, so they are serine-threonine kinases. The consensus sequence for the phosphorylation site in the amino acid sequence of a CDK substrate is [S/T*]PX[K/R], where S/T* is the phosphorylated serine or threonine, P is proline, X is any amino acid, K is lysine, and R is arginine.

Cyclin-dependent kinase complex

A cyclin-dependent kinase complex is a protein complex formed by the association of an inactive catalytic subunit of a protein kinase, cyclin-dependent kinase (CDK), with a regulatory subunit, cyclin. Once cyclin-dependent kinases bind to cyclin, the formed complex is in an activated state. Substrate specificity of the activated complex is mainly established by the associated cyclin within the complex. Activity of CDKCs is controlled by phosphorylation of target proteins, as well as binding of inhibitory proteins.

Maturation-promoting factor (abbreviated MPF, also called mitosis-promoting factor or M-Phase-promoting factor) is the cyclin-Cdk complex that was discovered first in frog eggs. It stimulates the mitotic and meiotic phases of the cell cycle. MPF promotes the entrance into mitosis (the M phase) from the G2 phase by phosphorylating multiple proteins needed during mitosis. MPF is activated at the end of G2 by a phosphatase, which removes an inhibitory phosphate group added earlier.

Restriction point

The restriction point (R), also known as the Start or G1/S checkpoint, is a cell cycle checkpoint in the G1 phase of the animal cell cycle at which the cell becomes "committed" to the cell cycle, and after which extracellular signals are no longer required to stimulate proliferation. The defining biochemical feature of the restriction point is the activation of G1/S- and S-phase cyclin-CDK complexes, which in turn phosphorylate proteins that initiate DNA replication, centrosome duplication, and other early cell cycle events. It is one of three main cell cycle checkpoints, the other two being the G2-M DNA damage checkpoint and the spindle checkpoint.

Cell cycle checkpoint

Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, with progression through the various phases of the cell cycle occurring only when favorable conditions are met. There are many checkpoints in the cell cycle, but the three major ones are: the G1 checkpoint, also known as the Start or restriction checkpoint or Major Checkpoint; the G2/M checkpoint; and the metaphase-to-anaphase transition, also known as the spindle checkpoint. Progression through these checkpoints is largely determined by the activation of cyclin-dependent kinases by regulatory protein subunits called cyclins, different forms of which are produced at each stage of the cell cycle to control the specific events that occur therein.

SCF complex

Skp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has important roles in the ubiquitination of proteins involved in the cell cycle. The SCF complex also marks various other cellular proteins for destruction.

Cyclin D

Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition. Cyclin D protein is anywhere from 155 to 477 amino acids in length.

Cyclin-dependent kinase 2

Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the CDK2 gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein kinases. This protein kinase is highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, also known as Cdk1 in humans. It is a catalytic subunit of the cyclin-dependent kinase complex, whose activity is restricted to the G1-S phase of the cell cycle, where cells make proteins necessary for mitosis and replicate their DNA. This protein associates with and is regulated by the regulatory subunits of the complex including cyclin E or A. Cyclin E binds G1 phase Cdk2, which is required for the transition from G1 to S phase while binding with Cyclin A is required to progress through the S phase. Its activity is also regulated by phosphorylation. Multiple alternatively spliced variants and multiple transcription initiation sites of this gene have been reported. The role of this protein in G1-S transition has been recently questioned as cells lacking Cdk2 are reported to have no problem during this transition.

Cyclin-dependent kinase 4 Human protein

Cyclin-dependent kinase 4 also known as cell division protein kinase 4 is an enzyme that in humans is encoded by the CDK4 gene. CDK4 is a member of the cyclin-dependent kinase family.

Cyclin-dependent kinase 6

Cell division protein kinase 6 (CDK6) is an enzyme encoded by the CDK6 gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of the cyclin-dependent kinase, (CDK) family, which includes CDK4. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression in the point of regulation named R or restriction point.

Cyclin-dependent kinase 1 Mammalian protein found in Homo sapiens

Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein that functions as a serine/threonine kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S. pombe, where it is encoded by genes cdc28 and cdc2, respectively. In humans, Cdk1 is encoded by the CDC2 gene. With its cyclin partners, Cdk1 forms complexes that phosphorylate a variety of target substrates ; phosphorylation of these proteins leads to cell cycle progression.

Polo-like kinases (Plks) are regulatory serine/threonin kinases of the cell cycle involved in mitotic entry, mitotic exit, spindle formation, cytokinesis, and meiosis. Only one Plk is found in the genomes of fruit flies (Polo), budding yeast (Cdc5) and fission yeast (Plo1). Vertebrates, however, have many Plk family members including Plk1, Plk2/Snk, Plk3/Prk/FnK, Plk4/Sak and Plk5. Of the vertebrate Plk family members, the mammalian Plk1 has been most extensively studied. During mitosis and cytokinesis, Plks associate with several structures including the centrosome, kinetochores, and the central spindle.

Cdc6

Cdc6, or cell division cycle 6, is a protein in eukaryotic cells. It is mainly studied in the budding yeast Saccharomyces cerevisiae. It is an essential regulator of DNA replication and plays important roles in the activation and maintenance of the checkpoint mechanisms in the cell cycle that coordinate S phase and mitosis. It is part of the pre-replicative complex (pre-RC) and is required for loading minichromosome maintenance (MCM) proteins onto the DNA, an essential step in the initiation of DNA synthesis. In addition, it is a member of the family of AAA+ ATPases and highly related to ORC1; both are the same protein in archaea.

Wee1

Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe. Wee1 has a molecular mass of 96 kDa and is a key regulator of cell cycle progression. It influences cell size by inhibiting the entry into mitosis, through inhibiting Cdk1. Wee1 has homologues in many other organisms, including mammals.

A series of biochemical switches control transitions between and within the various phases of the cell cycle. The cell cycle is a series of complex, ordered, sequential events that control how a single cell divides into two cells, and involves several different phases. The phases include the G1 and G2 phases, DNA replication or S phase, and the actual process of cell division, mitosis or M phase. During the M phase, the chromosomes separate and cytokinesis occurs.

Cell division control protein 4

Cdc4 is a substrate recognition component of the SCF ubiquitin ligase complex, which acts as a mediator of ubiquitin transfer to target proteins, leading to their subsequent degradation via the ubiquitin-proteasome pathway. Cdc4 targets primarily cell cycle regulators for proteolysis. It serves the function of an adaptor that brings target molecules to the core SCF complex. Cdc4 was originally identified in the model organism Saccharomyces cerevisiae. CDC4 gene function is required at G1/S and G2/M transitions during mitosis and at various stages during meiosis.

Control of chromosome duplication

In cell biology, eukaryotes possess a regulatory system that ensures that DNA replication occurs only once per cell cycle.

Clb5 and Clb6 are B-type, S-phase cyclins in yeast that assist in cell cycle regulation. Clb5 and Clb6 bind and activate Cdk1, and high levels of these cyclins are required for entering S-phase. S-phase cyclin binding to Cdk1 directly stimulates DNA replication as well as progression to the next phase of the cell cycle.

Mitotic Exit is an important transition point that signifies the end of mitosis and the onset of new G1 phase for a cell, and the cell needs to rely on specific control mechanisms to ensure that once it exits mitosis, it never returns to mitosis until it has gone through G1, S, and G2 phases and passed all the necessary checkpoints. Many factors including cyclins, cyclin-dependent kinases (CDKs), ubiquitin ligases, inhibitors of cyclin-dependent kinases, and reversible phosphorylations regulate mitotic exit to ensure that cell cycle events occur in correct order with fewest errors. The end of mitosis is characterized by spindle breakdown, shortened kinetochore microtubules, and pronounced outgrowth of astral (non-kinetochore) microtubules. For a normal eukaryotic cell, mitotic exit is irreversible.

References

  1. ↑ Schwob E, Böhm T, Mendenhall MD, Nasmyth K (October 1994). "The B-type cyclin kinase inhibitor p40SIC1 controls the G1 to S transition in S. cerevisiae". Cell. 79 (2): 233–44. doi:10.1016/0092-8674(94)90193-7. PMID   7954792. S2CID   34939988.
  2. ↑ Morgan DO (1997). The Cell Cycle: Principles of Control. London: New Science Press. pp. 200–1. ISBN   978-0-87893-508-6.
  3. ↑ Tripodi F, Zinzalla V, Vanoni M, Alberghina L, Coccetti P (August 2007). "In CK2 inactivated cells the cyclin dependent kinase inhibitor Sic1 is involved in cell-cycle arrest before the onset of S phase". Biochemical and Biophysical Research Communications. 359 (4): 921–7. doi:10.1016/j.bbrc.2007.05.195. PMID   17574209.
  4. 1 2 Cross FR, Schroeder L, Bean JM (July 2007). "Phosphorylation of the Sic1 inhibitor of B-type cyclins in Saccharomyces cerevisiae is not essential but contributes to cell cycle robustness". Genetics. 176 (3): 1541–55. doi:10.1534/genetics.107.073494. PMC   1931548 . PMID   17483408.
  5. ↑ Verma R, Annan RS, Huddleston MJ, Carr SA, Reynard G, Deshaies RJ (October 1997). "Phosphorylation of Sic1p by G1 Cdk required for its degradation and entry into S phase". Science. 278 (5337): 455–60. Bibcode:1997Sci...278..455V. doi:10.1126/science.278.5337.455. PMID   9334303.
  6. ↑ Toyn JH, Johnson AL, Donovan JD, Toone WM, Johnston LH (January 1997). "The Swi5 transcription factor of Saccharomyces cerevisiae has a role in exit from mitosis through induction of the cdk-inhibitor Sic1 in telophase". Genetics. 145 (1): 85–96. PMC   1207787 . PMID   9017392.
  7. ↑ Calzada A, Sacristán M, Sánchez E, Bueno A (July 2001). "Cdc6 cooperates with Sic1 and Hct1 to inactivate mitotic cyclin-dependent kinases". Nature. 412 (6844): 355–8. Bibcode:2001Natur.412..355C. doi:10.1038/35085610. PMID   11460169. S2CID   4410112.
  8. 1 2 3 4 Nash P, Tang X, Orlicky S, Chen Q, Gertler FB, Mendenhall MD, Sicheri F, Pawson T, Tyers M (November 2001). "Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication". Nature. 414 (6863): 514–21. Bibcode:2001Natur.414..514N. doi:10.1038/35107009. PMID   11734846. S2CID   16924667.
  9. ↑ Nishizawa M, Kawasumi M, Fujino M, Toh-e A (September 1998). "Phosphorylation of sic1, a cyclin-dependent kinase (Cdk) inhibitor, by Cdk including Pho85 kinase is required for its prompt degradation". Molecular Biology of the Cell. 9 (9): 2393–405. doi:10.1091/mbc.9.9.2393. PMC   25506 . PMID   9725902.
  10. ↑ Escoté X, Zapater M, Clotet J, Posas F (October 2004). "Hog1 mediates cell-cycle arrest in G1 phase by the dual targeting of Sic1". Nature Cell Biology. 6 (10): 997–1002. doi:10.1038/ncb1174. PMID   15448699. S2CID   19846318.
  11. ↑ Coccetti P, Zinzalla V, Tedeschi G, Russo GL, Fantinato S, Marin O, Pinna LA, Vanoni M, Alberghina L (August 2006). "Sic1 is phosphorylated by CK2 on Ser201 in budding yeast cells". Biochemical and Biophysical Research Communications. 346 (3): 786–93. doi:10.1016/j.bbrc.2006.05.171. PMID   16777072.
  12. 1 2 3 4 5 6 7 8 9 Kõivomägi M, Ord M, Iofik A, Valk E, Venta R, Faustova I, Kivi R, Balog ER, Rubin SM, Loog M (December 2013). "Multisite phosphorylation networks as signal processors for Cdk1". Nature Structural & Molecular Biology. 20 (12): 1415–24. doi:10.1038/nsmb.2706. PMC   3855452 . PMID   24186061.
  13. 1 2 3 4 5 6 7 8 9 Kõivomägi M, Valk E, Venta R, Iofik A, Lepiku M, Balog ER, Rubin SM, Morgan DO, Loog M (October 2011). "Cascades of multisite phosphorylation control Sic1 destruction at the onset of S phase". Nature. 480 (7375): 128–31. Bibcode:2011Natur.480..128K. doi:10.1038/nature10560. PMC   3228899 . PMID   21993622.
  14. ↑ Barberis M, De Gioia L, Ruzzene M, Sarno S, Coccetti P, Fantucci P, Vanoni M, Alberghina L (May 2005). "The yeast cyclin-dependent kinase inhibitor Sic1 and mammalian p27Kip1 are functional homologues with a structurally conserved inhibitory domain". The Biochemical Journal. 387 (Pt 3): 639–47. doi:10.1042/BJ20041299. PMC   1134993 . PMID   15649124.
  15. ↑ Khoo ML, Freeman JL, Witterick IJ, Irish JC, Rotstein LE, Gullane PJ, Asa SL (March 2002). "Underexpression of p27/Kip in thyroid papillary microcarcinomas with gross metastatic disease". Archives of Otolaryngology–Head & Neck Surgery. 128 (3): 253–7. doi: 10.1001/archotol.128.3.253 . PMID   11886339.
  16. ↑ Mann DJ, Child ES, Swanton C, Laman H, Jones N (February 1999). "Modulation of p27(Kip1) levels by the cyclin encoded by Kaposi's sarcoma-associated herpesvirus". The EMBO Journal. 18 (3): 654–63. doi:10.1093/emboj/18.3.654. PMC   1171158 . PMID   9927425.
  17. ↑ Nitti D, Belluco C, Mammano E, Marchet A, Ambrosi A, Mencarelli R, Segato P, Lise M (December 2002). "Low level of p27(Kip1) protein expression in gastric adenocarcinoma is associated with disease progression and poor outcome". Journal of Surgical Oncology. 81 (4): 167–75, discussion 175–6. doi:10.1002/jso.10172. PMID   12451619.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.