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Cyclin-dependent protein kinase plays an important role in the cell cycle regulation. The decision of a cell to divide or not is a crucially important to the organism. When the cell division regulatory mechanism is defective and cells undergo unregulated division, then it results in catastrophic cancer such as gastrointestinal cancers. Proper cell division needs to be ordered sequence of biochemical events.
Oscillating Levels of Cyclin-dependent protein kinases
The families of protein kinase having activities that are changing in response to cellular changes are involved in the control of the timing of cell cycle. These kinases are heterodimers composed of a regulatory subunit cyclin and a catalytic subunit cyclin-dependent protein kinase (CDK).
The catalytic subunit is inactive unless cyclin binds to it. The catalytic site is opened only when cyclin binds to this kinase exposing a key residue in the active site accessible for catalysis. Some CDK activities show striking oscillations which are the result of four mechanisms that regulate CDK activity. The different checkpoints of the cell cycle are as follow.
Step 1: Regulation achieved by phosphorylation of CDKs
Phosphorylation and dephosphorylation of two critical residues in the protein Tyr15 and Thr160 strikingly affects the activity of cyclin-dependent protein kinase. Phosphorylation of Tyr15 residue located near the amino terminal of an ATP binding site inactivates the CDKs and prevents binding of ATP to the CDKs because of repulsion between negative charges of a phosphate group and ATP.
The CDK can only be activated when Tyr15 phosphate group is dephosphorylated by specific phosphatase. The CDK-activating kinase phosphorylates Thr160 in the T loop forcing it to come out or the substrate binding cleft that permits substrate binding and catalytic activity.
Step 2: Cyclin degrades in a controlled manner
Proteolytic breakdown of mitotic cyclins are highly specific and precisely timed and regulates cyclin-dependent protein kinase activity throughout the cell cycle. The progress of mitosis requires first, activation and then the destruction of cyclins A & B. this activates the catalytic subunit of M phase CDK.
However, these cyclins have destruction box near to their amino terminal which targets them for destruction. Destruction box recognizing-protein (DBRP) recognize and initiates progress of cyclin degradation of this destruction box for which binding of another protein ubiquitin is needed. The binding of ubiquitin is accomplished by ubiquitin kinase, a complex proteasome.
Step 3: Synthesis of CDKs and cyclins are highly regulated
The rate of synthesis of cyclin or CDK or both are regulated by a change in CDK activity for example when specific transcription factor E2F is present in a nucleus to activate transcription of genes of cyclins and CDKs then only cyclin D & E and CDK2 & CDK4 are synthesized. Synthesis of nuclear transcription factors essential to enzyme production involved in DNA replication and cell division are induced by extracellular signals such as growth factors and cytokines.
Nuclear proteins such as Jun & Fos transcription factor are phosphorylated by growth hormones and promotes synthesis of various gene products including cyclin D1, CDKs, E2F. one of these that is E2F controls the production of several enzymes involved in DNA synthesis and enable cells to enter the S phase.
Step 4: CDKs Inhibition
Specific protease inhibitors such as p21 finally bind to and inactivate specific CDKs. The activity of specific CDKs that control whether a cell will divide, differentiate, become permanently quiescent, or begin a new cycle after a period of quiescent, is modulated by these four control mechanisms.
Phosphorylation of critical proteins by Cyclin-dependent protein kinase C regulates cell division
A highly organized meshwork of intermediate filaments composed of the protein laminin maintains the structure of nuclear envelope. Before segregation of sister chromatids in mitosis, the nuclear membrane is partly broken down due to phosphorylation of laminin protein by CDKs causing laminin filament to depolymerize. ATP-driven actin-myosin protein contractile machinery is a kinase target that pinches a dividing cell into two equal parts during cytokinesis.
Cyclin-dependent protein kinase phosphorylates a small regulatory subunit of myosin after the division causing dissociation of myosin from actin filament and inactivates the contractile machinery, but subsequent dephosphorylation allows reassembly of the contractile apparatus for the next round of cytokinesis. The third and most important CDK substrate is the retinoblastoma protein pRb. This protein participates in a mechanism that arrests cell division in G1 when DNA is damaged or deleted.
To regulate cell division in response to a variety of stimuli, PRb functions in all cell types. Unphosphorylated pRb binds the transcription factor E2F so that E2F can not promote transcription of a group of genes necessary for DNA synthesis thereby stopping cell cycle to proceed from G1 to S phase. The pRb-E2F blocking mechanism is relieved only when cyclin E-CDK2 complex phosphorylates pRb.