The c-fos Proto-Oncogene Is a Target for Transactivation by the p53 Tumor Suppressor

Abstract

The p53 tumor suppressor gene is mutated in over 50% of human cancers, resulting in inactivation of the wild-type (wt) p53 protein. The most notable biochemical feature of p53 is its ability to act as a sequence-specific transcriptional activator. Through use of the suppression subtractive hybridization differential screening technique, we identified c-fos as a target for transcriptional stimulation by p53 in cells undergoing p53-mediated apoptosis. Overexpression of wt p53 induces c-fos mRNA and protein. Moreover, in vivo induction of c-fos in the thymus following whole-body exposure to ionizing radiation is p53 dependent. p53 responsiveness does not reside in the basal c-fos promoter. Rather, a distinct region within the c-fos gene first intron binds specifically to p53 and confers upon the c-fos promoter the ability to become transcriptionally activated by wt p53. Identification of c-fos as a specific target for transcriptional activation by p53 establishes a direct link between these two pivotal regulatory proteins and raises the possibility that c-fos contributes to some of the biological effects of p53.

p53 regulation by post-translational modification and nuclear retention in response to diverse stresses

“…This tumor suppressor maintains genetic stability by responding to multiple environmental stresses including DNA damage, ribonucleotide depletion, microtubule disruption, redox modulation, cell adhesion, and hypoxia, as well as genetic' stresses created by activated oncogenes (reviewed in Giaccia and . These diverse stimuli appear to invoke a similar set of responses to achieve p53 activation: p53 must ®rst accumulate in the nucleus, and then bind to DNA as a tetramer to transcriptionally regulate a growing list of target genes including p21, GADD45, cyclin G, 14-3-3sigma, thrombospondin 1, MDM2, IGF-BP3, and bax (reviewed in Gottlieb and Oren, 1996;Ko and Prives, 1996), as well as c-fos (Elkeles et al, 1999) and others. However, depending on the stress and cell type, p53 activation can lead to responses as di erent as a reversible cycle arrest, induction of a senescent-like state, or apoptosis.…”

AP-1 subunits: quarrel and harmony among siblings

“…Although the link between the AP-1 and the p53 pathways appears complex, it seems possible that AP-1 factors have developed multiple ways of regulating p53 action. Under some circumstances, p53 can even induce expression of AP-1 components such as Fos (Elkeles et al, 1999), which suggests that p53 activity can act upstream of AP-1 signalling and adds further complexity to the AP-1/p53 network.…”

A novel p53 mutational hotspot in skin tumors from UV-irradiated Xpc mutant mice alters transactivation functions

“…The T122?L and the R270?C alleles failed to repress the c-Fos promoter. The first intron of the c-Fos gene also contains a p53 RE and wild-type p53 at near physiological levels of expression can activate a construct that includes the luciferase reporter gene fused to this region (Elkeles et al, 1999). The T122?L allele, but not R270?C, activated this RE, though at reduced levels compared to wild-type p53 protein ( Figure 3a).…”