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13.4Regulation of Cell Proliferation

Cell proliferation is regulated by the extracellular environment, such as the presence of nutrients, which plays a critical role in the proliferation of unicellular organisms. In multicellular organisms, however, nutrients are not the only extracellular environmental factor playing an important role. The internal environment of multicellular organisms is constantly and appropriately maintained, with energy and oxygen supplied, waste and CO2 removed, and other factors such as temperature and pH maintained at appropriate levels (see Selection 1 and 2 of Chapter 5 Homeostasis). Despite such an optimal environment, cells in multicellular organisms do not proliferate uncontrollably, because cell proliferation is regulated in a more advanced manner. What mechanisms are involved in the regulation of cell proliferation necessary to maintain the integrity of multicellular organisms?

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13.4.1

Positive and negative control

It is known that tissues made of somatic cells include many cells that do not proliferate (i.e. in the G0 phase) in normal circumstances, but proliferate only as needed. Cell proliferation in multicellular eukaryotes is regulated strictly through the balance of negative and positive cell proliferation signals. For instance, cells adhere closely to each other in the epithelial tissues of mammals, including humans (see Chapter 11), which controls proliferation negatively. If adhesion to the next cell is lost due to an injury such as a scratch on the skin, the negative control is lost—thus allowing proliferation. However, this event alone does not initiate proliferation. Cell proliferation is triggered only when the positive cell proliferation signals are sent to the cells by proliferative factors (or growth factors; many of which are proteins) that are specific to the cell type. If cells adhere properly to each other, proliferation is not initiated despite the presence proliferative factors. Thus, initiation of cell proliferation is regulated by positive and negative signals.

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Assembly of the DNA replication fork

Entry into the S phase is initiated by the activation of the pre-replicative complex. Recent studies have elucidated that the activation process involves numerous complicated reactions. Firstly, Cdc6, Cdt1, and the mini-chromosome maintenance (MCM) complex bind to the origin recognition complex (ORC), which binds specifically to the origins of replication on chromosomes, thereby forming the pre-replicative complex. The pre-replicative complex is then phosphorylated and activated by the Cdc7 kinase and CDK during the G1 phase, and the activated pre-replicative complex further binds with Cdc45, followed by the Dpb11/Cut5-Sld2 complex, and replication initiation factors such as GINS. Finally, following the activation of DNA helicase and binding of DNA polymerase, the replication fork is formed, which allows initiation of DNA replication (Column Figure 13-4).

Column Figure 13-4 Initiation of DNA replication

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13.4.2

Molecular machinery allowing positive and negative regulation

It is known that tissues made of somatic cells include many cells that do not proliferate (i.e. in the G0 phase) in normal circumstances, but proliferate only as needed. Cell proliferation in multicellular eukaryotes is regulated strictly through the balance of negative and positive cell proliferation signals. For instance, cells adhere closely to each other in the epithelial tissues of mammals, including humans (see Chapter 11), which controls proliferation negatively. If adhesion to the next cell is lost due to an injury such as a scratch on the skin, the negative control is lost—thus allowing proliferation. However, this event alone does not initiate proliferation. Cell proliferation is triggered only when the positive cell proliferation signals are sent to the cells by proliferative factors (or growth factors; many of which are proteins) that are specific to the cell type. If cells adhere properly to each other, proliferation is not initiated despite the presence proliferative factors. Thus, initiation of cell proliferation is regulated by positive and negative signals.

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13.4.3

Signal transduction leading up to the initiation of cell proliferation

Figure 13-8 illustrates the intracellular signal transduction (signaling cascade) that starts when proliferation inducing signals (positive proliferation signals) reach the cell membrane receptor. Cell proliferation is initiated through this process. The transcription factor synthesized by a newly expressed early gene further induces the expression of various protein genes. Among the genes expressed as a result, here too, CDKs and cyclins are the most important. These two proteins are synthesized and accumulated to form cyclin-CDK complexes. If they are activated, they phosphorylate other proteins (such as the Rb protein), activate transcription factors (such as E2F) of the genes required for DNA synthesis, and finally activate enzymes that synthesize the DNA materials necessary in the S phase, thereby allowing the cell cycle transition to the S phase.

Fig. 13-8 Signal transduction up to S-phase initiation

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Cell cycle and cancer

In most human cancer cells mutations of oncogenes and tumor suppressor genes (see Selection 2 of Chapter 15) cause abnormality in the regulation of proliferation and, subsequently, deregulated cell proliferation. Deregulated cell proliferation means uncontrolled proliferation of cells due to the absence of important regulatory mechanisms to maintain a normal cell count that is essential to all living organisms. In other words, even in an extracellular environment in which cell proliferation should be inhibited, cancer cells wake from their quiescent state and start proliferating.

The close relation between cancer and regulation of the initiation of cell proliferation can be well understood from the fact that the genes involved in the control of the initiation of cell proliferation are indeed oncogenes and tumor suppressor genes. For instance, genes such as Rb and p53, which function at the beginning of cell proliferation, are known to be tumor suppressor genes, whereas genes such as cyclin D1 are known to be oncogenes. When genes such as Rb, p53, and cyclin D1 mutate, normal regulation of cell proliferation is disabled, allowing cells to proliferate in a disorderly manner.

Another relation between the cell cycle and cancer can be observed at the DNA damage checkpoint. It is known that DNA damage checkpoint factors such as ATM/R and Chk2t are tumor suppressor genes. The p53 protein is also involved in the DNA damage checkpoint mechanism. Given that replication of damaged DNA promotes chromatin remodeling, which may trigger cancer, the DNA damage checkpoint is considered to not only contribute to the stability of the genome but also to control the occurrence of tumor initiation at the systemic level.

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