Abstract
Inactivation of the Arf-Mdm2-p53 tumor suppressor pathway is a necessary event for tumorigenesis. Arf controls Mdm2, which in turn regulates p53, but Arf and Mdm2 also have p53-independent functions that affect tumor development. Moreover, inhibition of oncogene-induced tumorigenesis relies on Arf and p53, but the requirements of Arf and p53 in tumor development initiated in the absence of overt oncogene overexpression and the role of Mdm2 in this process remain unclear. In a series of genetic experiments in mice with defined deficiencies in Arf, Mdm2 and/or p53, we show Mdm2 haploinsufficiency significantly delayed tumorigenesis in mice deficient in Arf and p53. Mdm2 heterozygosity significantly inhibited tumor development in the absence of Arf, and in contrast to Myc oncogene-driven cancer, this delay in tumorigenesis could not be rescued with the presence of one allele of Arf. Notably, Mdm2 haploinsufficieny blocked the accelerated tumor development in Arf deficient mice caused by p53 heterozygosity. However, tumorigenesis was not inhibited in Mdm2 heterozygous mice lacking both alleles of p53 regardless of Arf status. Surprisingly, loss of Arf accelerated tumor development in p53-null mice. Tumor spectrum was largely dictated by Arf and p53 status with Mdm2 haploinsufficiency only modestly altering the tumor type in some of the genotypes and not the number of primary tumors that arose. Therefore, the significant effects of Mdm2 haploinsufficiency on tumor latency were independent of Arf and required at least one allele of p53, and an Mdm2 deficiency had minor effects on the types of tumors that developed. These data also demonstrate that decreased levels of Mdm2 are protective in the presence of multiple genetic events in Arf and p53 genes that normally accelerate tumorigenesis.
Highlights
The Mdm2 oncogene is an essential regulator of tumorigenesis in part due to its control over the tumor suppressor p53, which is inactivated in half of all human malignancies [1,2]
Our study indicates Mdm2 heterozygosity can influence tumor development in the presence of p53, we did not test whether this outcome on tumorigenesis of Mdm2 haploinsufficiency was dependent on p53
We repeated this on a new cohort of mice and obtained similar results (Fig. 1A, Table 1); it is unclear what role p53 has in this delay in tumor development attributed to an Mdm2 haploinsufficiency
Summary
The Mdm oncogene is an essential regulator of tumorigenesis in part due to its control over the tumor suppressor p53, which is inactivated in half of all human malignancies [1,2]. Mdm binds to p53 and inhibits its transcriptional activity. The second protein encoded in the Ink4a locus, is a regulator of Mdm2 [3]. Arf binds to Mdm and blocks Mdm from inhibiting p53. Arf is frequently inactivated in human malignancies. The Arf-Mdm2p53 tumor suppressor pathway itself is activated by cellular stress, such as hyperproliferative signals from oncogenes, DNA damage, hypoxia, and many more, resulting in apoptosis, cell cycle block, or senescence, which protects genome integrity and inhibits tumorigenesis [4,5,6]
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