Cell cycle enzyme synthesis

HU is an inhibitor of ribonucleotide reductase, a rate-limiting enzyme which catalyzes the conversion of ribonucleotides into deoxyribonucleotides. HU is thus a cytotoxic agent as it has the ability to inhibit DNA synthesis. Consequently, H U can affect only cells that are actively synthesizing DNA and, therefore, a drug of S-phase cell-cycle specific. Moreover, HU-mediated inhibition of ribonucleotide reductase is reversible, implying that the action of HU will exhibit a relatively straight forward concentration-time course dependence [2—4-]. 

Myc Transcription factor A transcription factor that increases concentrations of the enzymes reqnired for S-phase of cell cycle, so that DNA synthesis can proceed withont any limitation in precnrsor concentrations (chapter 20). 

Figure 21.6 One mechanism of activation of the cell cycle by a growth factor. Binding of growth factor to its receptor activates membrane-bound phospholipase-C. This hydrolyses phosphati-dylinositol bisphosphate in the membrane to produce the messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 results in release of Ca from an intracellular store. The increased Ca + ion concentration activates protein kinases including protein kinase-C (PK-C). DAG remains membrane-bound and also activates protein kinase-C (PK-C) which remains in the activated form as it travels through the cell where it phosphory-lates and activates transcription factors. This results in activation of genes that express enzymes involved in nucleotide synthesis, DNA polymerases and cyclins, which are all reguired for the cell cycle (See Chapter 20 for provision of nucleotides and cyclins for the cell cycle).

Doxorubicin binds tightly to DNA by its ability to intercalate between base pairs and therefore is preferentially concentrated in nuclear structures. Intercalation results in steric hindrance, hence production of single-strand breaks in DNA and inhibition of DNA synthesis and DNA-dependent RNA synthesis. The enzyme topoisomerase II is thought to be involved in the generation of DNA strand breaks by the anthracydines. Cells in S-phase are most sensitive to doxorubicin, although cytotoxicity also occurs in other phases of the cell cycle. 

Hydroxyurea (Hydrea) inhibits the enzyme ribonucleotide reductase and thus depletes intracellular pools of deoxyribonucleotides, resulting in a specific impairment of DNA synthesis. The drug therefore is an S-phase specific agent whose action results in an accumulation of cells in the late Gj- and early S-phases of the cell cycle. 

FIGURE 12-43 Variations in the activities of specific CDKs during the cell cycle in animals. Cyclin E-CDK2 activity peaks near the G1 phase-S phase boundary, when the active enzyme triggers synthesis of enzymes required for DNA synthesis (see Fig. 12-46). Cyclin A-CDK2 activity rises during the S and G2 phases, then drops sharply in the M phase, as cyclin B-CDK1 peaks. 

Reoviruses 248. See also front cover Repair systems 16 Replication cycle. See Cell cycle Repression of enzyme synthesis 536, 538, 539 Repressor(s) 76, 239... 

Enzyme Synthesis Also Contributes to Regulation of Deoxyribonucleotides during the Cell Cycle Intracellular Concentrations of Nucleotides Vary According to the Physiological State of the Cell... 

Enzyme Synthesis Also Contributes to Regulation of Deoxyribonucleotides during the Cell Cycle... 

Many of the enzymes participating in de novo synthesis of deoxyribonucleotide triphosphates, as well as those responsible for interconversion of deoxyribonucleotides, increase in activity when cells prepare for DNA synthesis. The need for increased DNA synthesis occurs under three circumstances (1) when the cell proceeds from the G0, or resting, stage of the cell cycle to the S, or synthetic or replication, stage (fig. 23.26) (2) when it performs repair after extensive DNA damage and (3) after infection of quiescent cells with virus. When cells leave G0, for example, enzymes such as thymidylate synthase and ribonucleotide reductase, increase as well as the corresponding mRNAs. These increases in enzyme amount supplement allosteric controls that increase the activity of each enzyme molecule. Corresponding decreases in amounts of these enzymes and their mRNAs occur when DNA synthesis is completed. 

Cells which have spent a long time in Gl lose some of the enzymes typically present in dividing cells — particularly those concerned with DNA synthesis. These cells have traditionally been said to be out of cycle or in GO. The implication of the GO-phase is that to leave GO-cells require a stimulus to urge them past a barrier and back into cycle. Pardee (1974) has suggested that whenever cells are exposed to suboptimal physiological conditions they enter a quiescent phase, and that there is a single restriction point in Gl which regulates their re-entry into a new round of the cell cycle. 

A wide range of iron chelators have been shown to inhibit ribonucleotide reductase [79,80] and this is undoubtedly the reason for cytotoxic properties of many such molecules. Some iron chelators may also function as free radical scavengers, for instance, hydroxyurea which inhibits the enzyme by the latter mode of action. Such agents hold the cell cycle in the S-stage because the synthesis of DNA is inhibited. The ability of iron chelators to inhibit ribonucleotide reductase has led to several proposals for therapeutic application. 

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