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Role of Smad4 (DPC4) inactivation in human cancer

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Abstract

The tumor suppressor gene Smad4 (DPC4) at chromosome 18q21.1 belongs to the Smad family, which mediates the TGFβ signaling pathway suppressing epithelial cell growth. This review summarizes the mutational events of the Smad4 gene in human cancer. The Smad4 gene is genetically responsible for familial juvenile polyposis, an autosomal dominant disease characterized by predisposition to gastrointestinal polyps and cancer. In this syndrome, polyps are formed by inactivation of the Smad4 gene through germline mutation and loss of the unaffected wild-type allele. In pancreatic and colorectal cancer, inactivation of the Smad4 gene through homozygous deletion or intragenic mutation occurs frequently in association with malignant progression. However, mutation of this gene is seen only occasionally in the rest of human cancers. The majority of Smad4 gene mutations in human cancer are missense, nonsense, and frameshift mutations at the mad homology 2 region (MH2), which interfere with the homo-oligomer formation of Smad4 protein and the hetero-oligomer formation between Smad4 and Smad2 proteins, resulting in disruption of TGFβ signaling. Supporting evidence for the above observation was provided by genetically manipulated mice carrying either a heterozygote of the Smad4 gene or a compound heterozygote of the Smad4 and APC genes, which develop either gastrointestinal polyps/cancer mimicking familial juvenile polyposis or progressed colorectal cancer, respectively.

Section snippets

Isolation of the DPC4 gene and its identification as a member of the Smad family

Smad4 was first identified as a tumor suppressor gene of pancreatic cancer by Harn et al. in 1996 and designated as DPC4 (homozygously deleted in pancreatic carcinoma, locus 4) [1]. Nearly 90% of pancreatic cancer show loss of heterozygosity (LOH) at chromosome 18q [2], in which the candidate tumor suppressor gene DCC (deleted in colorectal carcinoma) is located. Since mutation of the DCC gene has not been found in pancreatic and other cancers, a search for a novel target gene of the 18qLOH was

Smad proteins and TGFβ signaling

Smad proteins are the critical components of the TGFβ signaling pathway, which negatively regulates the growth of epithelial cells (for a review see [4]). As illustrated in Fig. 1, TGFβ signals are transduced by two kinds of receptors, Receptor I and II, which have serine/threonine kinase activity. Upon the binding of TGFβ to TGFβRII, this receptor activates TGFβRI by phosphorylation. TGFβRI in turn phosphorylates the intracellular target Smad2 or Smad3. These proteins have an SSXS motif in

Germline mutation of the Smad4 gene in familial juvenile polyposis

Familial juvenile polyposis is an autosomal dominant disease characterized by predisposition to hamartomatous polyps and gastrointestinal cancer. This disease usually occurs during childhood. In 1998, Howe et al. [7] reported germline mutations in the Smad4 gene among 5 of 9 familial juvenile polyposis families, suggesting that Smad4 is the causative gene of this disease. To date, germline mutations have been detected in nearly 20 families and account for 25–60% of the cases analyzed. The

Somatic alterations of the Smad4 gene in pancreatic cancer

Prior to isolation of the DPC4 gene, the same group demonstrated in 1995 frequent LOH at chromosomes 1p (70%), 9p (80%), 17p (90%), and 18q (90%) by an allelotype analysis of 18 xenografts of human pancreatic cancer [2]. This suggested that possible tumor suppressor genes are present in these regions. As mentioned above, the tumor suppressor gene, Smad4, was identified at the homozygously deleted region 18q21.1. Additional genetic alterations in pancreatic cancer include mutations of the K-ras

Somatic alterations of the Smad4 gene in colorectal cancer

In 1990, Fearon and Vogelstein [15] proposed multi-stage genetic alterations in colorectal carcinogenesis, typically in an adenoma–carcinoma sequence. In this sequence, the APC gene (5q) is inactivated at an early stage, followed by activation of the K-ras gene during the development of moderate to severe adenoma, and inactivation of the p53 gene (17p) at the stage of conversion from adenoma to carcinoma. Additional frequent LOH at chromosomes 1p, 8p, 18q, and 22q suggests that inactivation of

Somatic alterations of the Smad4 gene in various types of human cancer

Table 1 summarizes the Smad4 gene alterations in various human cancers. Somatic alteration of the Smad4 gene is, as mentioned above, most prevalent in pancreatic and colorectal cancer. Intragenic mutations were less frequently observed in acute myeloid leukemia, biliary tract carcinoma, ovarian cancer, and small intestinal carcinoma, and occasionally in gastric carcinoma, head/neck squamous carcinoma, hepatocellular carcinoma, and lung carcinoma.

As shown in Fig. 3, the majority of Smad4 gene

Mutations of other members of the Smad family

Mutations of the Smad2 gene, located at 18q21, have been detected in the MH2 domain in colorectal and other human cancers, but their frequency being far less than those of the Smad4 gene [37]. Mutations of Smad3 (15q21), Smad6 (15q21), and Smad7 (18q21) genes have not been detected so far in human cancers.

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