Dmp1 is haplo-insufficient for tumor suppression and modifies the frequencies of Arf and p53 mutations in Myc-induced lymphomas

Autor: Jerold E. Rehg, Kazushi Inoue, Frederique Zindy, David H. Randle, Charles J. Sherr
Rok vydání: 2001
Předmět:
Zdroj: Genesdevelopment. 15(22)
ISSN: 0890-9369
Popis: Induction of p53-dependent transcription after genotoxic stress or oncogene activation leads to expression of genes that trigger either cell cycle arrest or apoptosis, thereby guarding against tumor formation (Levine 1997). The central role of p53 in tumor suppression is underscored by the fact that about half of human cancers have p53 mutations, whereas many of the remainder exhibit particular alterations in other genes, such as Mdm2 and Arf, which disable p53 function. The best characterized negative regulator of p53 is Mdm2, which ubiquitinates p53 and targets its proteolytic destruction (Prives 1998; Juven-Gershon and Oren 1999). Because Mdm2 is itself a p53-inducible gene, it participates in a negative feedback loop that helps to terminate the p53 response. In turn, by antagonizing functions of Mdm2, the product of the Arf tumor suppressor gene (p19Arf in mouse and p14ARF in humans) stabilizes p53 and enhances its activity (Sherr 1998; Sharpless and DePinho 1999). Arf is induced by oncogenes such as Myc, E1A, Ras, and v-Abl, and also by overexpression of E2F transcription factors whose normal role is to control the temporal expression of genes required for DNA replication. By monitoring the strength of mitogenic signals, Arf prevents hyperproliferation by diverting incipient cancer cells to alternative fates—namely, p53-dependent growth arrest, or more dramatically, apoptosis. Arf disruption in mice predisposes to spontaneous tumor development (Kamijo et al. 1997) and enhances the rate at which mouse strains sustaining other oncogenic lesions develop tumors (Chin et al. 1997; Holland et al. 1998; Eischen et al. 1999; Jacobs et al. 1999b; Schmitt et al. 1999). Pertinent to studies described below, more than half of the Burkitt-type B-cell lymphomas arising in Eμ-Myc transgenic mice were found to sustain p53 mutations (28%) or biallelic Arf deletions (24%), whereas others lacking overt Arf or p53 mutations overexpressed Mdm2 (16%) (Eischen et al. 1999). The 25-wk mean latency for tumor formation in Eμ-Myc transgenic mice was halved on the Arf+/− background, and 80% of the resulting lymphomas lost the wild-type Arf allele. Arf-null, Eμ-Myc transgenic animals developed more aggressive lympholeukemias and died by only 8 wk of age. Together, these results emphasize the role of the Arf–Mdm2–p53 pathway in protecting against tumor emergence. However, we also observed that some Eμ-Myc lymphomas that had deleted the Arf gene or sustained p53 mutations overexpressed Mdm2, implying that the Arf–Mdm2–p53 pathway is not strictly linear. Moreover, about a quarter of the lymphomas arising in Eμ-Myc transgenic mice exhibited no identifying genetic lesion in Arf, Mdm2, or p53, suggesting that other mechanisms may deregulate the pathway. A series of transcription factors other than E2F and Myc govern Arf expression. These include other positively acting factors, such as Dmp1 (see below) and β-catenin/Tcf (M. Oren, pers. comm.) that bind directly to the Arf promoter to induce transcription, as well as proteins such as Bmi-1 (Jacobs et al. 1999a), Tbx-2 (Jacobs et al. 2000), Twist (Maestro et al. 1999), Jun D (Weitzman et al. 2000), and p53 itself (Kamijo et al. 1998; Stott et al. 1998), which negatively regulate Arf through as yet ill-defined mechanisms. Overexpression of Twist and Tbx-2 in human rhabdomyosarcomas and breast carcinomas, respectively, suggests that active ARF repression might contribute to tumorigenesis. Epigenetic silencing of the ARF promoter has also been observed in human cancers (Esteller et al. 2001). Dmp1 was isolated in a two-hybrid interactive screen using cyclin D2 as bait, and it encodes a 120- to 130-kD nuclear phosphoprotein with a central DNA-binding domain containing three Myb-like repeats flanked by acidic transactivation domains at both termini (Hirai and Sherr 1996; Inoue and Sherr 1998). The human and murine orthologs share 95% amino-acid sequence identity and are completely conserved throughout their Myb-like repeats (Bodner et al. 1999). Dmp1 binds to nonameric Ets consensus sequences in DNA (CCCG[G or T]ATGT) and competes with Ets-family proteins for sites that contain the GGA core. DNA binding can be antagonized by the interaction of Dmp1 with D-type, but not other cyclins. Despite the frequency of potential Dmp1-binding sites in mammalian genomes, its binding to a single site in the proximal Arf promoter induces p19Arf-dependent cell cycle arrest (Inoue et al. 1999). Conversely, Arf expression is dampened in Dmp1-null mouse embryo fibroblasts (MEFs), which resist cellular senescence, do not rapidly accumulate p53 mutations, and are susceptible to transformation by oncogenic Ras (Inoue et al. 2000). Dmp1-null mice did not spontaneously develop cancers in their first year of life but were susceptible to carcinogen- and radiation-induced tumors, implying that by regulating Arf function, Dmp1 may have tumor-suppressing activities (Inoue et al. 2000). Here, we show that Dmp1 is a bona fide tumor suppressor gene whose loss obviates the selection for Arf deletion or p53 mutation that normally occurs during Myc-induced lymphomagenesis.
Databáze: OpenAIRE
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