p53 Requires the Stress Sensor USF1 to Direct Appropriate Cell Fate Decision

Abstract

Genomic instability is a major hallmark of cancer. To maintain genomic integrity, cells are equipped with dedicated sensors to monitor DNA repair or to force damaged cells into death programs. The tumor suppressor p53 is central in this process. Here, we report that the ubiquitous transcription factor Upstream Stimulatory factor 1 (USF1) coordinates p53 function in making proper cell fate decisions. USF1 stabilizes the p53 protein and promotes a transient cell cycle arrest, in the presence of DNA damage. Thus, cell proliferation is maintained inappropriately in Usf1 KO mice and in USF1-deficient melanoma cells challenged by genotoxic stress. We further demonstrate that the loss of USF1 compromises p53 stability by enhancing p53-MDM2 complex formation and MDM2-mediated degradation of p53. In USF1-deficient cells, the level of p53 can be restored by the re-expression of full-length USF1 protein similarly to what is observed using Nutlin-3, a specific inhibitor that prevents p53-MDM2 interaction. Consistent with a new function for USF1, a USF1 truncated protein lacking its DNA-binding and transactivation domains can also restore the induction and activity of p53. These findings establish that p53 function requires the ubiquitous stress sensor USF1 for appropriate cell fate decisions in response to DNA-damage. They underscore the new role of USF1 and give new clues of how p53 loss of function can occur in any cell type. Finally, these findings are of clinical relevance because they provide new therapeutic prospects in stabilizing and reactivating the p53 pathway.

Association between single nucleotide polymorphisms of upstream transcription factor 1 (USF1) and susceptibility to papillary thyroid cancer

“…Nonetheless, under stress conditions such as DNA damage, oxidative stress, hypoxia and oncogene expression, USF1 impedes MDM2‐mediated p53 degradation, which enhances the stability of p53 and facilitates cell cycle arrest, DNA repair or apoptosis (Fig. ) . Hence, the implication of USF1 in p53 pathway suggested that USF1 may have other functions independent of the well‐established role as a transcriptional factor.…”

“…2). 39 Hence, the implication of USF1 in p53 pathway suggested that USF1 may have other functions independent of the well-established role as a transcriptional factor. Alternatively, USF1 suppresses the expression of human telomerase reverse transcriptase (hTERT) in oral cancer cells.…”

p53 regulation upon genotoxic stress: intricacies and complexities

“…Studies have shown that USF1 is equally as efficient as Nutlin-3a treatment and superior to other transcription factors such ATF3 and TFII31 in p53 stabilization during genotoxic stress. 34 Taken together, these findings indicate that ubiquitylationdependent pathways ensure minimal levels of p53 in normal cells whereas inhibition of these factors by messengers of DNA damage induces p53 to protect cells from transformation-inducing alterations.…”

UV‐B‐activated B16 melanoma cells or HaCaT keratinocytes accelerate signaling pathways associated with melanogenesis via ANGPTL 2 induction, an activity antagonized by Chrysanthemum extract

“…Therefore, we undertook analysis of the Angptl2 promoter using the UCSC genome browser and observed binding motifs for many transcription factors that may potentially regulate Angptl2 . Among them is USF1, a transcription factor induced by UV‐B, as well as the cAMP response element binding protein (CREB) . We conclude that CE extracts may inhibit ANGPTL2 by intefering with USF1 transcriptional activity, a mechanism we will explore in future studies.…”