Related Experiment Video
Updated: Aug 19, 2026
Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Tumor susceptibility of Rassf1a knockout mice
Stella Tommasi1, Reinhard Dammann, Zhongqiu Zhang
1Division of Biology, City of Hope National Medical Center, Duarte, CA 91010, USA.
Abstract:
The human Ras association domain family 1 (RASSF1) gene is located at 3p21.3 in an area that is believed to harbor at least one important tumor suppressor gene. The two major isoforms of RASSF1, RASSF1A and RASSF1C, are distinguished by alternative NH(2)-terminal exons and the two transcripts initiate in two separate CpG islands. RASSF1A is one of the most frequently inactivated genes described thus far in human solid tumors. Inactivation of RASSF1A most commonly involves methylation of the promoter and CpG island associated with the RASSF1A isoform. In contrast, RASSF1C is almost never inactivated in tumors. Here, we have derived Rassf1a knockout mice in which exon 1-alpha of the Rassf1 gene was deleted, leading to specific loss of Rassf1a but not Rassf1c transcripts. Rassf1a-targeted mice were viable and fertile. Rassf1a(-/-) mice were prone to spontaneous tumorigenesis in advanced age (18-20 months). Whereas only two tumors developed in 48 wild-type mice, six tumors were found in 35 Rassf1a(+/-) mice (P < 0.05) and thirteen tumors were found in 41 Rassf1a(-/-) mice (P < 0.001). The tumors in Rassf1a-targeted mice included lung adenomas, lymphomas, and one breast adenocarcinoma. Rassf1a(-/-) and wild-type mice were treated with two chemical carcinogens, benzo(a)pyrene and urethane, to induce skin tumors and lung tumors, respectively. Rassf1a(-/-) and Rassf1a(+/-) mice showed increased tumor multiplicity and tumor size relative to control animals. The data are consistent with the tumor-suppressive role of Rassf1a, which may explain its frequent epigenetic inactivation in human tumors.
Insights
The Ras association domain family 1A (RASSF1A) gene acts as a tumor suppressor. Loss of RASSF1A in mice increases spontaneous tumor development and susceptibility to carcinogens, supporting its role in preventing cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The Ras association domain family 1 (RASSF1) gene, located at 3p21.3, is implicated in tumor suppression.
- RASSF1A is frequently inactivated in human solid tumors, primarily through promoter methylation.
- RASSF1C, an alternative isoform, is rarely inactivated in tumors.
Purpose of the Study:
- To investigate the in vivo tumor suppressor role of Rassf1a.
- To determine if Rassf1a deficiency leads to increased susceptibility to chemically induced tumorigenesis.
Main Methods:
- Generation of Rassf1a knockout mice with specific deletion of exon 1-alpha.
- Monitoring spontaneous tumor development in wild-type, heterozygous, and homozygous knockout mice.
- Treatment of mice with chemical carcinogens (benzo(a)pyrene and urethane) to assess tumor induction.
Main Results:
- Rassf1a knockout mice exhibited increased rates of spontaneous tumor formation, including lung adenomas, lymphomas, and breast adenocarcinoma.
- Heterozygous and homozygous Rassf1a-deficient mice showed significantly higher tumor multiplicity and size after exposure to carcinogens compared to wild-type controls.
- Tumorigenesis was observed in aged Rassf1a knockout mice, indicating a role in preventing cancer progression.
Conclusions:
- Rassf1a functions as a critical tumor suppressor, consistent with its frequent epigenetic inactivation in human cancers.
- Loss of Rassf1a function predisposes to both spontaneous and carcinogen-induced tumor development.
- These findings highlight the importance of RASSF1A in maintaining genomic integrity and preventing oncogenesis.
More Related Videos
07:13Initiation of Metastatic Breast Carcinoma by Targeting of the Ductal Epithelium with Adenovirus-Cre: A Novel Transgenic Mouse Model of Breast Cancer
Published on: March 26, 2014
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
Related Concept Videos
02:38The Ras Gene
Ras is a superfamily...
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
02:43Mouse Models of Cancer Study
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...
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...
01:24Small GTPases - Ras and Rho
Three regulatory proteins control their activity:
02:23Abnormal Proliferation