Cyclin-dependent Kinase Inhibitor
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A cyclin-dependent kinase inhibitor protein (also known as CKIs, CDIs, or CDKIs) is a protein that inhibits the enzyme
cyclin-dependent kinase Cyclin-dependent kinases (CDKs) are a predominant group of serine/threonine protein kinases involved in the regulation of the cell cycle and its progression, ensuring the integrity and functionality of cellular machinery. These regulatory enzym ...
(CDK) and Cyclin activity by stopping the
cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
if there are unfavorable conditions, therefore, acting as tumor suppressors. Cell cycle progression is stopped by Cyclin-dependent kinase inhibitor protein at the G1 phase. CKIs are vital proteins within the control system that point out whether the processes of DNA synthesis,
mitosis Mitosis () is a part of the cell cycle in eukaryote, eukaryotic cells in which replicated chromosomes are separated into two new Cell nucleus, nuclei. Cell division by mitosis is an equational division which gives rise to genetically identic ...
, and cytokines control one another. When a malfunction hinders the successful completion of DNA synthesis in the G1 phase, it triggers a signal that delays or halts the progression to the S phase. Cyclin-dependent kinase inhibitor proteins are essential in the regulation of the cell cycle. If cell
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s surpass the cell cycle checkpoints during cell cycle regulation, it can result in various types of cancer.


CKI Inactivation Process

Cyclin-dependent kinase inhibitor proteins work by inactivating the CDKs through degradation. The typical inactivation mechanism of the CDK/Cyclin complex is based on binding a CDK inhibitor to the CDK cyclin complex and a partial conformational rotation of the CDK. The cyclin is thus forced to release the T loop and detach from the CDK. Then, the CDK inhibitor initiates a small helix into the cleft, blocking the cleft and blocking the active site of the CDK. Eventually, it releases the ATP out of the aperture of the CDK and deactivates it. Cyclin-dependent kinase inhibitor proteins use ATP as a
phosphate Phosphates are the naturally occurring form of the element phosphorus. In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthop ...
contributor to
phosphorylate In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...
serine and threonine residues.   Human cells contain many different cyclins that bind to different CDKs. CDKs and cyclins appear and activate at specific cell cycle phases. Seven cyclin-dependent kinase inhibitor proteins have been identified. They are p15,
p16 p16 (also known as p16INK4a, cyclin-dependent kinase inhibitor 2A, CDKN2A, multiple tumor suppressor 1 and numerous other synonyms), is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the ...
, p18, p19, p21, p27, and p57. These cyclin-dependent kinase inhibitor proteins emerge only in their specific cell cycle phase. Each Cyclin/CDK complex is specific to the part of the cell cycle phase. Each CDK and cyclin can be identified based on the location of the cell cycle. CKIs fall into two categories; those that inhibit CDK1, CDK2, and CDK5 and those that inhibit CDK4 and CDK6. These checkpoints' cell cycle blocks at both the G1/S and G2/M checkpoints are consistent with the inhibition profiles of the enzymes. ----


Discovery

The discovery of Cyclin-dependent kinase inhibitor proteins in 1990 opened the door in how we think about cell cycle control. It has steered to various other fields of study such as
developmental biology Developmental biology is the study of the process by which animals and plants grow and develop. Developmental biology also encompasses the biology of Regeneration (biology), regeneration, asexual reproduction, metamorphosis, and the growth and di ...
,
cell biology Cell biology (also cellular biology or cytology) is a branch of biology that studies the structure, function, and behavior of cells. All living organisms are made of cells. A cell is the basic unit of life that is responsible for the living an ...
and
cancer research Cancer research is research into cancer to identify causes and develop strategies for prevention, diagnosis, treatment, and cure. Cancer research ranges from epidemiology, molecular bioscience to the performance of clinical trials to evaluate ...
. The discovery of the first CKIs in yeast ( Far1) and P21 in mammals has led to research on family of molecules. Further research has demonstrates that Cdks, cyclins and CKIs play essential roles in processes such as transcription, epigenetic regulation,
metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
, stem cell self-renewal, neuronal functions and
spermatogenesis Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testicle. This process starts with the Mitosis, mitotic division of the stem cells located close to the basement membrane of ...
. In mammals, p27, a cyclin-dependent kinase inhibitor protein, helps control CDK activity in G1. Also, the INK4 proteins help stop the G1-CDK activity when they encounter anti-proliferative signals within the environment.  CKIs help promote the specific inhibitory signals that contain the cell from entering the S phase. In budding yeast, SIC 1 and Roughex, RUX, in ''Drosophila'' possess the same contributions that contribute to the stability of G1 cells. They are expressed in higher numbers in G1 cells to make sure that no S or M CDKs are in the cell. ----


Structure

In the cyclin-dependent kinase (CDK) family, or CDK, Cyclin, and CKIs, serine/threonine kinases play an integral role in regulating the eukaryotic cell cycle. The structure of
CDK2 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 serine/threonine ...
-CyclinA and p27 is determined by crystallography, demonstrating that the inhibitor of p27 stretches at the top of the Cyclin-CDK complex. The amino terminal of p27 has an RXL motif exhibiting a hydrophobic patch of cyclin A. The carboxyl-terminal end of the p27 fragment interacts with the
beta sheet The beta sheet (β-sheet, also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gene ...
of CDKs, causing interference with the structure; p27 slides into the ATP-binding site of CDK2 and inhibits ATP binding. ----


Clinical significance

Role in cancer: Cyclin-dependent kinase inhibitor (CKI) mutants are frequent in human cancers. The function of CKI is to stop cell growth when there are mistakes due to DNA damage. Once a cell is stopped at a checkpoint due to DNA damage, either the damage is repaired or the cell is induced to perform apoptosis. However, if CKI’s mutations don’t stop the cell,
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 transition, G1/S phase transition. Cyclin D protein is anywhere fro ...
is transcribed. It moves into the cytoplasm and eventually activates a specific cyclin-dependent kinase (CDK). The active cyclin/CDK complex then phosphorylates proteins, activates them, and sends the cell into the next phase of the cell cycle. Since the cell with damaged DNA is not stopped, the cell eventually moves out of the G1 checkpoint and prepares for DNA synthesis. When there is uncontrolled cell growth, it can lead to cancer cells due to the inactivation of the CKIs.


Associated gene and target


References


External links

* {{Cell cycle proteins Protein domains