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Mutations Causing Loss of Growth-Inhibiting and Cell-Cycle Controls

Normal growth and development depends on a finely tuned, highly regulated balance between growth-promoting and growth-inhibiting pathways. Mutations that disrupt this balance can lead to cancer. Most of the mutations discussed in the previous section cause inappropriate activity of growth-promoting pathways. Just as critical are mutations that decrease the activity of growth-inhibiting pathways when they are needed.

For example, transforming growth factor p (TGFp), despite its name, inhibits proliferation of many cell types, including most epithelial and immune system cells. Binding of TGFp to its receptor induces activation of cytosolic Smad transcription factors (see Figure 14-2). After translocating to the nucleus, Smads can promote expression of the gene encoding p15, which causes cells to arrest in G1. TGFp signaling also promotes expression of genes encoding extracellular matrix proteins and plasminogen activator inhibitor 1 (PAI-1), which reduces the plasmin-catalyzed degradation of the matrix. Loss-of-function mutations in either TGFp receptors or in Smads thus promote cell proliferation and probably contribute to the invasiveness and metastasis of tumor cells (Figure 23-20). Such mutations have in fact been found in a variety of human cancers, as we describe in Chapter 14.

The complex mechanisms for regulating the eukaryotic cell cycle are prime targets for oncogenic mutations. Both positive- and negative-acting proteins precisely control the entry of cells into and their progression through the cell cycle, which consists of four main phases: G1, S, G2, and mitosis (see Figure 21-2). This regulatory system assures the proper coordination of cellular growth during G1 and G2, DNA synthesis during the S phase, and chromosome segregation and cell division during mitosis. In addition, cells that have sustained damage to their DNA normally are arrested before their DNA is replicated. This arrest allows time for the DNA damage to be repaired; alternatively, the arrested cells are directed to commit suicide via programmed cell death. The whole cell-cycle control system functions to prevent cells from becoming cancerous. As might be expected, mutations in this system often lead to abnormal development or contribute to cancer.

Mutations That Promote Unregulated Passage from G1 to S Phase Are Oncogenic

Once a cell progresses past a certain point in late G1, called the restriction point, it becomes irreversibly committed to entering the S phase and replicating its DNA (see Figure 21-28). D-type cyclins, cyclin-dependent kinases (CDKs), and the Rb protein are all elements of the control system that regulate passage through the restriction point.

The expression of D-type cyclin genes is induced by many extracellular growth factors, or mitogens. These cyclins assemble with their partners CDK4 and CDK6 to generate catalytically active cyclin-CDK complexes, whose kinase activity promotes progression past the restriction point. Mi-togen withdrawal prior to passage through the restriction point leads to accumulation of p16. Like p15 mentioned above, p16 binds specifically to CDK4 and CDK6, thereby inhibiting their kinase activity and causing G1 arrest. Under normal circumstances, phosphorylation of Rb protein is initiated midway through G1 by active cyclin D-CDK4 and cy-clin D-CDK6 complexes. Rb phosphorylation is completed by other cyclin-CDK complexes in late G1, allowing activation of E2F transcription factors, which stimulate transcription of genes encoding proteins required for DNA synthesis. The complete phosphorylation of Rb irreversibly commits the cell to DNA synthesis. Most tumors contain an onco-genic mutation that causes overproduction or loss of one of the components of this pathway such that the cells are propelled into the S phase in the absence of the proper extracellular growth signals (Figure 23-21).

Elevated levels of cyclin D1, for example, are found in many human cancers. In certain tumors of antibody-producing B lymphocytes, for instance, the cyclin D1 gene is translocated such that its transcription is under control of an antibody-gene enhancer, causing elevated cyclin D1 production throughout the cell cycle, irrespective of extracellular signals. (This phenomenon is analogous to the c-myc translocation in Burkitt's lymphoma cells discussed earlier.) That cyclin D1 can function as an oncoprotein was shown by studies with transgenic mice in which the cyclin D1 gene was

Type II receptors

Type I receptors

Type II receptors

Type I receptors

Nucleus

Transcription of gene encoding cell-cycle inhibitor

Decreased production of PAI-1 allows increased extracellular matrix degradation and, hence, metastasis

Nucleus

Transcription of gene encoding cell-cycle inhibitor

Decreased production of PAI-1 allows increased extracellular matrix degradation and, hence, metastasis

PAI-1 promoter \K

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