Transcription of gene encoding inhibitor of protease that degrades extracellular matrix proteins

Transcription of gene encoding inhibitor of protease that degrades extracellular matrix proteins

▲ FIGURE 23-20 Effect of loss of TGFp signaling.

Binding of TGFp, an antigrowth factor, causes activation of Smad transcription factors. In the absence of TGFp signaling due to either a receptor mutation or a SMAD mutation, cell proliferation and invasion of the surrounding extracellular matrix (ECM) increase. [See X. Hua et al., 1998, Genes & Develop. 12:3084.]

placed under control of an enhancer specific for mammary ductal cells. Initially the ductal cells underwent hyperprolif-eration, and eventually breast tumors developed in these transgenic mice. Amplification of the cyclin D1 gene and concomitant overproduction of the cyclin D1 protein is common in human breast cancer.

The proteins that function as cyclin-CDK inhibitors play an important role in regulating the cell cycle (Chapter 21). In particular, loss-of-function mutations that prevent p16 from

▲ FIGURE 23-21 Restriction point control.

Unphosphorylated Rb protein binds transcription factors collectively called E2F and thereby prevents E2F-mediated transcriptional activation of many genes whose products are required for DNA synthesis (e.g., DNA polymerase). The kinase activity of cyclin D-CDK4 phosphorylates Rb, thereby activating E2F; this kinase activity is inhibited by p16. Overproduction of cyclin D, a positive regulator, or loss of the negative regulators p16 and Rb, commonly occurs in human cancers.

inhibiting cyclin D-CDK4/6 kinase activity are common in several human cancers. As Figure 23-21 makes clear, loss of p16 mimics overproduction of cyclin D1, leading to Rb hy-perphosphorylation and release of active E2F transcription factor. Thus p16 normally acts as a tumor suppressor. Although the p16 tumor-suppressor gene is deleted in some human cancers, in others the p16 sequence is normal. In these latter cancers (e.g., lung cancer), the p16 gene is inactivated by hypermethylation of its promoter region, which prevents transcription. What promotes this change in the methylation of p16 is not known, but it prevents production of this important cell-cycle control protein.

We've seen already that inactivating mutations in both RB alleles lead to childhood retinoblastoma, a relatively rare type of cancer. However, loss of RB gene function also is found in more common cancers that arise later in life (e.g., carcinomas of lung, breast, and bladder). These tissues, unlike retinal tissue, most likely produce other proteins whose function is redundant with that of Rb, and thus loss of Rb is not so critical. Several proteins are known that are related in structure and probably function to Rb. In addition to inactivating mutations, Rb function can be eliminated by the binding of an inhibitory protein, designated E7, that is encoded by human papillomavirus (HPV), another nasty viral trick to create virus-producing tissue.

Tumors with inactivating mutations in Rb generally produce normal levels of cyclin D1 and functional p16 protein. In contrast, tumor cells that overproduce cyclin D1 or have lost p16 function generally retain wild-type Rb. Thus loss of only one component of this regulatory system for controlling passage through the restriction point is all that is necessary to subvert normal growth control and set the stage for cancer.

Loss-of-Function Mutations Affecting Chromatin-Remodeling Proteins Contribute to Tumors

Mutations can undermine growth control by inactivating tumor-suppressor genes, but these genes can also be silenced by repressive chromatin structures. In recent years the importance of chromatin-remodeling machines, such as the Swi/Snf complex, in transcriptional control has become increasingly clear. These large and diverse multiprotein complexes have at their core an ATP-dependent helicase and often control acetylation of histones. By causing changes in the positions or structures of nucleosomes, Swi/Snf complexes make genes accessible or inaccessible to DNA-binding proteins that control transcription (Chapter 11). If a gene is normally activated or repressed by Swi/Snf-mediated chro-matin changes, mutations in the genes encoding the Swi or Snf proteins will cause changes in expression of the target gene.

Our knowledge of the target genes regulated by Swi/Snf and other such complexes is incomplete, but the targets evidently include some growth-regulating genes. For example, studies with transgenic mice suggest that Swi/Snf plays a role in repressing the E2F genes, thereby inhibiting progression through the cell cycle. The relationship between the genes that encode Swi/Snf proteins and the E2F gene was discovered in genetic experiments with flies. Transgenic flies were constructed to overexpress E2F, which resulted in mild growth defects. A search for mutations that increase the effect of the E2F overexpression in these flies identified three components of the Swi/Snf complex. That loss of function of these genes increases the proliferative effects of E2F indicates that Swi/Snf normally counteracts the function of the E2F transcription factor. Thus loss of Swi/Snf function, just like loss of Rb function, can lead to overgrowth and perhaps cancer. Indeed, in mice, Rb protein recruits Swi/Snf proteins to repress transcription of the E2F gene.

With chromatin-remodeling complexes involved in so many cases of transcriptional control, it is expected that Swi/Snf and similar complexes will be linked to many cancers. In humans, for example, mutations in Brg1, which encodes the Swi/Snf catalytic subunit, have been found in prostate, lung, and breast tumors. Components of the Swi/Snf complex also have been found to associate with BRCA1, a nuclear protein that helps suppress human breast cancer. BRCA-1 is involved in the repair of double-strand DNA breaks (discussed in the final section of this chapter) and in transcriptional control, so the Swi/Snf complex may assist BRCA-1 in these functions.

Loss of p53 Abolishes the DNA-Damage Checkpoint

A critical feature of cell-cycle control is the G1 checkpoint, which prevents cells with damaged DNA from entering the

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