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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/11/29 23:19:54」(JST)

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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. Cyclins 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 microarrays 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.

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English Journal

Sodium selenate, a protein phosphatase 2A activator, mitigates hyperphosphorylated tau and improves repeated mild traumatic brain injury outcomes.

Tan XL1, Wright DK2, Liu S1, Hovens C3, O'Brien TJ1, Shultz SR4.
Neuropharmacology.Neuropharmacology.2016 Sep;108:382-93. doi: 10.1016/j.neuropharm.2016.05.001. Epub 2016 May 7.
Mild traumatic brain injuries may result in cumulative brain damage and neurodegenerative disease. To date, there is no pharmaceutical intervention known to prevent these consequences. Hyperphosphorylated tau has been associated in this process, and protein phosphatase 2A 55 kDa regulatory B subuni
PMID 27163189

LRRK2 Promotes Tau Accumulation, Aggregation and Release.

Guerreiro PS1,2, Gerhardt E2, Lopes da Fonseca T1,2, Bähr M3, Outeiro TF4,5,6, Eckermann K3.
Molecular neurobiology.Mol Neurobiol.2016 Jul;53(5):3124-35. doi: 10.1007/s12035-015-9209-z. Epub 2015 May 27.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are known as the most frequent cause of familial Parkinson's disease (PD), but are also present in sporadic cases. The G2019S-LRRK2 mutation is located in the kinase domain of the protein, and has consistently been reported to promote a gain
PMID 26014385

Exosomes in Alzheimer's disease.

Malm T1, Loppi S1, Kanninen KM2.
Neurochemistry international.Neurochem Int.2016 Jul;97:193-9. doi: 10.1016/j.neuint.2016.04.011. Epub 2016 Apr 27.
Exosomes, nano-sized extracellular vesicles secreted by most cell types, are found everywhere in the body. The role of exosomes in cellular functions has in the past years developed from being considered little more than cellular trashcans, to being proven important intercellular messengers and nota
PMID 27131734

Japanese Journal

Alzheimers Disease and Prion Protein

Zhou Jiayi,Liu Bingqian
Intractable & Rare Diseases Research 2(2), 35-44, 2013
… Alzheimers disease (AD) is a devastating neurodegenerative disease with progressive loss of memory and cognitive function, pathologically hallmarked by aggregates of the amyloid-beta (Aβ) peptide and hyperphosphorylated tau in the brain. …
NAID 130003397559

Molecular Approaches to the Treatment, Prophylaxis, and Diagnosis of Alzheimer's Disease: Tangle Formation, Amyloid-β, and Microglia in Alzheimer's Disease

Takata Kazuyuki,Kitamura Yoshihisa
Journal of pharmacological sciences 118(3), 331-337, 2012-03-20
… NFTs are formed by the intraneuronal accumulation of hyperphosphorylated tau, and progressive synaptic and neuronal losses closely correlate with cognitive deficits in AD. …
NAID 10030455494

Risk of Japanese carriers of hyperphosphorylated paratarg-7, the first autosomal-dominantly inherited risk factor for hematological neoplasms, to develop monoclonal gammopathy of undetermined significance and multiple myeloma

GRASS Sandra,IIDA Shinsuke,WIKOWICZ Aleksandra,PREUSS Klaus-Dieter,INAGAKI Atsushi,SHIMIZU Kazuyuki,ZIEPERT Marita,UEDA Ryuzo,PFREUNDSCHUH Michael
Cancer science 102(3), 565-568, 2011-03-10
NAID 10029291102