Disruption of the ARF transcriptional activator DMP1 facilitates cell immortalization, Ras transformation, and tumorigenesis

• DOI: 10.1101/gad.14.14.1797
• Publication Date: 2021-11-15T03:33:18Z
• Authors: Kazushi Inoue; Renren Wen; Jerold E. Rehg; Masashi Adachi; John L. Cleveland; Martine F. Roussel; Charles J. Sherr
• Keywords: Null cell

The DMP1 transcription factor induces the ARF tumor suppressor gene in mouse fibroblasts, leading to cell cycle arrest a p53-dependent manner. We disrupted sequences encoding DNA-binding domain of embryonic stem cells and derived animals lacking functional protein. DMP1-null are small at birth, males develop more slowly than their wild-type littermates. Some adult exhibit seizures and/or obstuctive uropathy, each unknown cause. growth explanted embryo fibroblasts (MEFs) is progressively retarded as passaged culture on defined transfer protocols; but, unlike behavior normal cells, p19(ARF), Mdm2, p53 levels remain relatively low MEFs do not senesce. Whereas establishment lines from usually always accompanied by either or loss function, continuously readily give rise established 3T3 3T9 that retain genes. Early-passage like ARF-null p53-null mice, can be morphologically transformed oncogenic Ha-Ras (Val-12) alone. Splenic lymphocytes harvested both mice enhanced proliferative responses long-term cultures when stimulated divide with antibody CD3 interleukin-2. Although only 1 40 spontaneously developed first year life, neonatal treatment dimethylbenzanthracene ionizing radiation induced tumors various histologic types were observed similarly treated DMP1(+/+) animals. Karyotypic analyses lymphomas revealed pseudodiploid chromosome numbers, consistent retention p53. Together, these data suggest function compromised, but eliminated, DMP1.