Related Experiment Video
Updated: Aug 6, 2026
Fluorescence-based Monitoring of PAD4 Activity via a Pro-fluorescence Substrate Analog
Published on: November 5, 2014
Role of Smad4 (DPC4) inactivation in human cancer
Michiko Miyaki1, Toshio Kuroki
1Tokyo Metropolitan Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan.
Abstract:
The tumor suppressor gene Smad4 (DPC4) at chromosome 18q21.1 belongs to the Smad family, which mediates the TGFbeta 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 TGFbeta 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.
Insights
The Smad4 tumor suppressor gene is frequently mutated in pancreatic and colorectal cancers, disrupting TGFbeta signaling. These mutations are key in familial juvenile polyposis and cancer progression.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Smad4 (DPC4) is a tumor suppressor gene in the Smad family, crucial for TGFbeta signaling that inhibits epithelial cell growth.
- Mutations in Smad4 are linked to familial juvenile polyposis, an inherited condition predisposing individuals to gastrointestinal polyps and cancer.
- The Smad4 gene is located at chromosome 18q21.1.
Purpose of the Study:
- To review and summarize the mutational events of the Smad4 gene in human cancers.
- To elucidate the role of Smad4 gene inactivation in the development and progression of gastrointestinal polyposis and cancer.
Main Methods:
- Review of existing literature on Smad4 gene mutations in human cancer.
- Analysis of genetic data from human cancer patients and genetically manipulated mouse models.
- Examination of mutation types (missense, nonsense, frameshift) and their locations, particularly within the mad homology 2 (MH2) region.
Main Results:
- Smad4 gene inactivation via germline mutation and allele loss drives polyp formation in familial juvenile polyposis.
- Homozygous deletion or intragenic mutation of Smad4 frequently occurs in pancreatic and colorectal cancer, correlating with malignant progression.
- The majority of Smad4 mutations occur in the MH2 region, disrupting protein oligomerization and TGFbeta signaling.
- Mouse models with Smad4 or Smad4/APC gene alterations recapitulate gastrointestinal polyposis and colorectal cancer phenotypes.
Conclusions:
- Smad4 gene mutations are a significant factor in the pathogenesis of familial juvenile polyposis and are frequently observed in pancreatic and colorectal cancers.
- Disruption of TGFbeta signaling due to Smad4 mutations, particularly in the MH2 domain, plays a critical role in cancer development and progression.
- Smad4's function as a tumor suppressor is consistently demonstrated across human cancers and validated in preclinical models.
Related Concept Videos
02:34Inhibition of Cdk Activity
02:23Abnormal Proliferation
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:31The Intrinsic Apoptotic Pathway
02:34Inhibition of CDK Activity
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...