Cell division protein kinase

AR - androgen (or dihydrotestosterone) receptor, CDK2/cyclin A - cell division protein kinase 2, DHFR - dihydrofolate reductase, ECFR - epidermal growth factor receptor, ER, ERa, and ER/i - estrogen... 

The cell cycle The concentrations of specific proteins regulate the cell cycle by activation (known as cyclins) is achieved of cell-division cycle kinases, during key steps in the cycle. The concentration of these proteins (cyclins) is regulated by synthesis and degradation. The latter is this proteolytic system (Chapter 20). 

The cyclin binds to a cyclin-dependent cell division cycle kinase (cdck). (In the absence of cyclin, this enzyme is sometimes known as a naked protein kinase.)... 

Figure 21.16 k diagram of the mechanism by which retinoblastoma protein (Rb) regulates transcription factor activity. The rb protein binds to the transcription factor, which forms a complex in which the transcription factor for three genes is inactive. Phosphorylation of Rb by a cell division cycle kinase results in dissociation of transcription factor from the complex and hence activation. 

Watanabe T, Ono Y, Taniyama Y, Hazama K, Igarashi K, Ogita K, Kikkawa U, Nishi-zuka Y (1992) Cdl division arrest induced by phorbol ester in CHO cells overexpressing protein kinase C-delta subspecies. Proc Natl Acad Sd USA 89 10159-10163... 

Winston N J 1997 Stability of cyclin B protein during meiotic maturation and the first mitotic cell division in mouse oocytes. Biol Cell 89 211-219 Winston NJ, Maro B 1995 Calmodulin-dependent protein kinase II is activated transiently in ethanol-stimulated mouse oocytes. Dev Biol 170 350-352 Winston NJ, Bourgain-Guglielmetti F, Ciemerych MA et al 2000 Early development of mouse embryos null mutant for the cyclin A2 gene occurs in the absence of maternally derived cyclin A2 gene products. Dev Biol 223 139-153... 

The reaction of X with S must be fast and reversible, close to if not at equilibrium with concentration of S. It can be that there is an intermediate step in which X binds to a protein kinase (a protein which phosphorylates other proteins mostly at histidine residues in bacteria) using phosphate transferred from ATP. It then gives XP which is the transcription factor, where concentration of S still decides the extent of phosphorylation. No change occurs in DNA itself. Here equilibrium is avoided as dephosphorylation involves a phosphatase, though changes must be relatively quick since, for example, cell cycling and division depend on these steps, which must be completed in minutes. We have noted that such mechanical trigger-proteins as transcription factors are usually based on a-helical backbones common to all manner of such adaptive conformational responses (Section 4.11). 

Cdc, cell division cycle DARPP-32, dopamine and cAMP-regulated phosphoprotein of 32kDa MAPK, mitogen-activated protein kinase NIPP1, nuclear inhibitor of PP1 PP, protein phosphatase Vffl, vaccinia virus. 

Recent experimental studies have uncovered a direct link between the cell cycle and circadian rhythms. Thus, the circadian clock protein BMALl induces the expression of the gene Weel, which codes for the protein kinase that inactivates through phosphorylation the kinase cdkl that controls the G2/M transition [149]. This link allows the coupling of cell division to the circadian clock and explains how the latter may entrain the cell cycle clock in a variety of cell types. 

As might be expected from other mechanisms of regulation described in this text, phosphorylation and dephosphorylation of key proteins is the main mechanism for regulating the cycle, i.e. reversible phosphorylation, also known as interconversion cycles (discussed in Chapter 3). In the cell cycle, several of these interconversion cycles play a role in control at the checkpoints. Two important terms must be appreciated to help understand the mechanism of regulation of the cycle the phosphorylation of proteins is catalysed by specific protein kinases, known as cell-division kinases (cdck) or cell cycle kinases (cck) and these enzymes are activated by specific proteins, known as cyclins. 

Unfortunately, this field is made difficult for a student by the terminology used by biochemists. For example, there is a protein kinase that regulates the cycle between G2 and M, i.e. the second restriction point. This protein is known as maturation (or mitosis) promoting factor, since it promotes entry into mitosis. It phosphorylates a protein, probably a transcription factor, in the nucleus. The kinase has a molecular mass of 34kDa. Hence it is known as p34 cell division kinase, abbreviated to p34-cdc and, since it is regulated at restriction point 2, it is known as p34-cdc-2 protein, which is sometimes written as p34°. This kinase is normally inactive until it binds a cyclin. Hence the active maturation-promoting factor is, in fact, a protein kinase-cyclin complex, which is referred to as p34° °-cyclin complex. It is hoped that this piece of information may help a student (or lecturer from another field) to understand one part of a review article that contains the abbreviation p34° -cyclin complex, without explanation, or other similar pieces of biochemical shorthand. 

Figure 21.14 A summary diagram of how damaged DNA leads to arrest of the cell cycle. Damaged DNA activates a protein kinase which phosphorylates and hence stabilises p53, which stimulates transcription of the p21 gene which expresses a protein that arrests the cycle. CDK, cell cycle division kinase.

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