Hyperphosphorylation
Encyclopedia
Hyperphosphorylation occurs when a biochemical with multiple phosphorylation
sites is fully saturated. Hyperphosphorylation is one of the signalling mechanisms used by the cell
to regulate mitosis
. When these mechanisms fail, developmental problems or cancer
are a likely outcome. The mechanism appears to be largely conserved throughout eukaryote
species.
The dynamics of mitosis are similar to a state machine. In a healthy cell, checkpoints between phases, permit a new phase to begin only when the previous phase is complete and successful. At these checkpoints, gatekeeper molecules block or allow events, depending on their level of phosphorylation. Kinases are responsible for adding phosphate groups and phosphatases for removing them. Cyclin
s are molecules that manage the timing of cell cycle events. Cyclin dependent kinases pair up with cyclins to become operational. Cyclins are named because they are created or destroyed at predetermined points within the cell cycle. Kinase inhibitors
add another level of modulation. Kinase inhibitors are grouped into classes and are assigned not very descriptive acronyms. These include INKS for inhibitors of kinase, KIPS for kinase inhibitors and CKIPS for cyclin dependent kinases inhibitors.
Scientists have used a variety of tools to unravel the role of hyperphosphorylation. These include the study of knockout genes, the use of antibodies to block receptors on particular molecules, the use of temperature sensitive mutants, and microarray
s to monitor the expression of particular genes. Yeast
are a popular species for study because of the rapid cell cycle.
Rb
is one of the most studied checkpoint molecules. It is so named because defects in Rb are linked to retinoblastoma
. In its unphosphorylated state it blocks the transition from G0 or resting state to S or synthesis. It does this in at least 3 ways. It inhibits RNA synthesis, it prevents chromosomes from unwinding and it binds E2F, a factor needed for DNA synthesis. When it is hyperphosphorylated, Rb becomes inactive, releasing bound E2F and allowing phase S to proceed.
Wee is a protein
that operates at the G2 to metaphase checkpoint. Wee becomes active if errors occur in the DNA synthesis phase. It blocks entry into metaphase until the problem is resolved. Like Rb, wee becomes inactive when hyperphosphorylated.
In contrast Mad1
is active when hyperphosphorylated. In its active state it is part of the checkpoint that blocks transition to anaphase. Cdc2, part of the metaphase entry checkpoint, is active depending on the pattern of phosphorylation.
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
sites is fully saturated. Hyperphosphorylation is one of the signalling mechanisms used by the cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
to regulate mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
. When these mechanisms fail, developmental problems or cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
are a likely outcome. The mechanism appears to be largely conserved throughout eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
species.
The dynamics of mitosis are similar to a state machine. In a healthy cell, checkpoints between phases, permit a new phase to begin only when the previous phase is complete and successful. At these checkpoints, gatekeeper molecules block or allow events, depending on their level of phosphorylation. Kinases are responsible for adding phosphate groups and phosphatases for removing them. Cyclin
Cyclin
Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase enzymes.- Function :...
s are molecules that manage the timing of cell cycle events. Cyclin dependent kinases pair up with cyclins to become operational. Cyclins are named because they are created or destroyed at predetermined points within the cell cycle. Kinase inhibitors
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
add another level of modulation. Kinase inhibitors are grouped into classes and are assigned not very descriptive acronyms. These include INKS for inhibitors of kinase, KIPS for kinase inhibitors and CKIPS for cyclin dependent kinases inhibitors.
Scientists have used a variety of tools to unravel the role of hyperphosphorylation. These include the study of knockout genes, the use of antibodies to block receptors on particular molecules, the use of temperature sensitive mutants, and microarray
Microarray
A microarray is a multiplex lab-on-a-chip. It is a 2D array on a solid substrate that assays large amounts of biological material using high-throughput screening methods.Types of microarrays include:...
s to monitor the expression of particular genes. Yeast
Yeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
are a popular species for study because of the rapid cell cycle.
Rb
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...
is one of the most studied checkpoint molecules. It is so named because defects in Rb are linked to retinoblastoma
Retinoblastoma
Retinoblastoma is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers , with more than nine out of every ten sufferers surviving into...
. In its unphosphorylated state it blocks the transition from G0 or resting state to S or synthesis. It does this in at least 3 ways. It inhibits RNA synthesis, it prevents chromosomes from unwinding and it binds E2F, a factor needed for DNA synthesis. When it is hyperphosphorylated, Rb becomes inactive, releasing bound E2F and allowing phase S to proceed.
Wee is a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that operates at the G2 to metaphase checkpoint. Wee becomes active if errors occur in the DNA synthesis phase. It blocks entry into metaphase until the problem is resolved. Like Rb, wee becomes inactive when hyperphosphorylated.
In contrast Mad1
Mad1
Mitotic spindle assembly checkpoint protein MAD1 is a protein that in humans is encoded by the MAD1L1 gene.MAD1L1 is also known as Human Accelerated Region 3. It may therefore have played a key role in differentiating Humans from Apes.-Interactions:...
is active when hyperphosphorylated. In its active state it is part of the checkpoint that blocks transition to anaphase. Cdc2, part of the metaphase entry checkpoint, is active depending on the pattern of phosphorylation.