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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

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Holland-Frei Cancer Medicine. 6th edition.

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The INK4A Locus and the p16 INK4A and p19 ARF Genes

, MD, PhD and , MD.

Studies of the INK4a locus on chromosome 9p illustrate well how observations from initially disparate lines of investigation often converge to implicate a particular locus as a critical factor in cancer development. LOH of chromosome 9p was frequently found in many different tumor types, including melanomas, gliomas, and nonsmall cell lung, bladder, and head and neck cancers, as well as leukemias.119–122 Of considerable interest were observations establishing that a subset of such tumors had homozygous (complete) deletions affecting the 9p21 region,123–125 strongly supporting the existence of a tumor suppressor gene in the region. In addition to the frequent somatic alterations of chromosome 9p sequences in cancers, linkage studies of some families with inherited melanoma indicated a melanoma predisposition gene mapped to essentially the same region of 9p.126

These observations stimulated great interest in the chromosome 9p region presumed to contain the tumor suppressor gene(s). One of the genes identified in the region as a result of positional cloning efforts was initially termed MTS1. 127 Sequence analysis of MTS1 showed that it was identical to a previously described gene, encoding the Cdk inhibitor protein known as p16.128 Because the p16 protein functioned by inhibiting Cdk4 and Cdk6, the protein was termed an INK4 protein. Another highly related gene, mapping immediately next to the p16/MTS1 gene on chromosome 9p, was found to encode a second INK4 protein, known as p15 (Figure 7-6). The gene encoding the p16 protein is most often termed INK4a and the gene for p15 is INK4b. 129, 130 Subsequent studies show that heterozygous mutations in INK4a are present in some patients with inherited melanoma, and in some families with inherited melanoma and pancreatic cancer.131–134 Somatic mutations in INK4a are present in a significant fraction of many different cancer types, including but not limited to melanomas, gliomas, pancreatic and bladder cancers, and leukemias. In some tumors, deletions affecting the INK4a gene also involve the INK4b gene. In rare tumors, deletions inactivate INK4b but not INK4a. 135 The prevalence and specific nature of INK4a mutations vary markedly from one tumor type to another. In contrast to other tumor-suppressor genes, like RB1 and p53, homozygous deletion is a fairly common mechanism of INK4a inactivation in cancer.136

Figure 7-6. Genomic structure, mutations, and transcripts of the INK4b (p15) and INK4a (p16/p19ARF) locus.

Figure 7-6

Genomic structure, mutations, and transcripts of the INK4b (p15) and INK4a (p16/p19ARF) locus. The origin of the p15, p16, and p19ARF transcripts is shown schematically, along with a representative depiction of genomic deletions, point mutations (arrows), (more...)

Detailed studies of the INK4a locus led to the identification of a novel alternative transcript containing nucleotide sequences identical to those in transcripts for the p16INK4a protein, but with unique 5′ sequences (see Figure 7-6).129, 130, 137 The alternative INK4a locus transcript encodes a protein known as p19ARF with p19 denoting its apparent molecular weight and ARF denoting alternative reading frame. The human version of the mouse p19ARF protein is sometimes referred to as p14ARF because of its smaller apparent molecular weight in gel electrophoresis studies. However, both proteins appear to have identical functions, and the discussion below uses the p19ARF terminology because it is found more frequently in the literature. The p19ARF protein contains sequences from a distinct first exon (exon 1β). Exon 1β is located upstream of exon 1α, the first exon present in transcripts for p16 (see Figure 7-6). Exon 1β is spliced to exon 2, which, along with exon 3, is present in the transcripts for both the p19ARF and p16INK4a proteins. However, the p19ARF protein shares no sequence similarity with the p16INK4a protein because p19ARF synthesis initiates at a unique methionine codon in exon 1β and continues through exon 2, using an alternative open reading frame with no similarity to the p16INK4a open reading frame. Careful studies of somatic and inherited mutations at the INK4a locus indicate that localized mutations inactivating the p16INK4a protein are common in human cancer, but that localized mutations inactivating p19ARF are uncommon.129, 130 However, the frequent occurrence of homozygous deletions at the INK4a locus implies that mutational inactivation of both proteins may be strongly selected for during tumor development (see Figure 7-6). Other findings suggest that p16INK4a and p19ARF expression may be lost in some tumor types as a result of methylation of DNA regulatory sequences at the INK4a locus (see Figure 7-6).138–140 Furthermore, studies of mice with germ line inactivation of p19ARF and p16INK4a indicate that these proteins function as tumor-suppressor genes in vivo.141–143

The mechanism through which the p16INK4a protein controls tumorigenic growth is apparently through its inhibition of Cdk4 activity. As indicated above, phosphorylation of pRb impedes its ability to transcriptionally regulate E2F-target genes (see Figure 7-4). The cyclin D1/Cdk4 complex has a critical role in regulating pRb phosphorylation and function.140 Hence, the p16INK4a protein, by virtue its regulation of Cdk4 activity, is, in turn, a critical factor in regulating pRb phosphorylation. Presumably, inactivation of p16INK4a results in inappropriate phosphorylation of pRb and a subsequent inability of hyperphosphorylated pRb to bind E2Fs and appropriately regulate gene expression at the G1/S transition.

Initially, insights into the means by which p19ARF functioned as a growth regulator and tumor suppressor in vitro and in vivo were lacking, in part because the p19ARF protein lacks significant similarity to proteins with well-established function. It is now clear that p19ARF binds directly to the MDM2 protein, and its binding blocks both MDM2-induced degradation of p53 and MDM2's effects on p53-mediated transcriptional activation of genes.130 Hence, p19ARF function is important for maintaining the appropriate function of p53 in cells, much like p16INK4a function is critical for appropriate pRb function. The findings on the functions of the p16INK4a and p19ARF proteins emphasize the concept that oncogenes and tumor-suppressor genes do not function in isolation. Rather, they function in intricately linked cascades/networks (Figure 7-7).98

Figure 7-7. Role of the p19ARF protein in checkpoint control.

Figure 7-7

Role of the p19ARF protein in checkpoint control. The p19ARF protein (ARF) responds to proliferative signals normally required for cell proliferation. When these signals exceed a critical threshold, the ARF-dependent checkpoint (vertical barrel) is activated, (more...)

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By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK13507

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