Transgenic and Knockout Mice Models to Reveal the Functions of Tumor Suppressor Genes

Abstract

Cancer is caused by multiple genetic alterations leading to uncontrolled cell proliferation through multiple pathways. Malignant cells arise from a variety of genetic factors, such as mutations in tumor suppressor genes (TSGs) that are involved in regulating the cell cycle, apoptosis, or cell differentiation, or maintenance of genomic integrity. Tumor suppressor mouse models are the most frequently used animal models in cancer research. The anti-tumorigenic functions of TSGs, and their role in development and differentiation, and inhibition of oncogenes are discussed. In this review, we summarize some of the important transgenic and knockout mouse models for TSGs, including Rb, p53, Ink4a/Arf, Brca1/2, and their related genes.

The Heart: Mostly Postmitotic or Mostly Premitotic? Myocyte Cell Cycle, Senescence, and Quiescence

“…Rb plays an important role in cell cycle exit and myocyte differentiation [59]. Rb-deficient mice are lethal [60], however, animals deficient in Rb and p130 have an increased heart-weight-to-body weight and show enhanced BrdU-incorporation and pH3-staining, indicating persistent myocyte division [61]. Although, the role and pattern of pocket proteins require more elucidation, there are hints towards a role of these proteins in myocyte cell cycle progression.…”

Cancer Genes and Chromosome Instability

“…Patients with Li-Fraumeni syndrome characterized by germline mutations of TP53 develop a wide range of malignancies (reviewed in [67]). Mice expressing the TP53 mutants have increased incidence of sarcomas and carcinomas (reviewed in [68,69]). In contrast, "super TP53" mice, carrying TP53 alleles in addition to the two endogenous alleles, exhibit an enhanced response to DNA damage and are significantly protected from cancer when compared with normal mice [70].…”

“…Cancer patients with missense mutations in TP53 often have a poorer prognosis than those lacking TP53 entirely, as the presence of dominantly mutated p53 not only confers loss of tumor suppressor activity but also provides a gain of oncogenic function [68,71]. P53 gain of oncogenic function mutants have enhanced oncogenic potential and effectively induce CIN [68,69,72]. In vitro and in vivo data have established that loss of p53 activity and, to a greater degree, dominantly mutated p53 is the major event responsible for increased expression of cell-cycle and proliferation-associated genes (reviewed in [73]).…”

“…Inactivation of INK4A, ARF or both genes strongly predisposes mice to tumor development (reviewed in [69]). Loss of p16 INK4A plays a causal role in centrosome dysfunction and the subsequent generation of CIN cells in multiple cell types [109].…”

“…Cell lines display a genetic drift and low heterogeneity different from tumors in vivo as a consequence of selection and adaptation for cell culture conditions [226,227]. Numerous tissue-specifc genetically engineered mouse cancer models have been developed that exhibit many biologic hallmarks of human cancer (reviewed in [69,228]), however, they still poorly reproduce spontaneous tumors (reviewed in [229]). In transgenic mice models all the cells share the same genetic defects, which can not be the case in most sporadic cancers.…”