TABLE 1.

Summary of p53 involvement in expression of the target PAI-1 gene.

1. TGF-β1 stimulates p53ser9/15 phosphorylation promoting binding of p-p53/SMAD3 complexes to the PAI-1 promoter in HK-2 human renal tubular epithelial cells (Overstreet et al., 2014).

2. Two canonical p53-binding motifs in the PAI-1 promoter (Kunz et al., 1995; Parra et al., 2001; Riley et al., 2008) meet the >90 p53MH score threshold required for the identification of potential p53-responsive genes (Hoh et al., 2002). Both p53-binding sites (nt −224 to −204) are proximal to the transcription start site.

3. PAI-1 is a member of the “high confidence” cohort of 151 p53 target genes (Chang et al., 2014).

4. PAI-1 ranks 131 among 343 of the most prominent p53-activated genes (Fischer, 2017).

5. PAI-1 is included in the p53 Target Database (Fischer, 2017).

6. PAI-1 is a component in the p53 circuit board (Sullivan et al., 2012).

7. p53 silencing, genetic ablation/subsequent rescue, and pharmacological inhibition confirmed that p53 is required for PAI-1 expression in TGF-β1-stimulated cells (Overstreet et al., 2014).

8. TGF-β1-initiated PAI-1 expression is attenuated in p53 knockdown cells (Cordenonsi et al., 2003).

9. p53–/– fibroblasts are not inducible for increased PAI-1 expression in response to TGF-β1 (Samarakoon et al., 2013a,b).

10. Pretreatment of Mv-1Lu mink lung cells (stably expressing a PAI-1 promoter-luciferase reporter construct) with the p53 inhibitor pifithrin-α effectively suppressed TGF-β1-dependent PAI-1 transcription (Samarakoon et al., 2013a,b).

11. Radiation-induced PAI-1 expression requires p53/SMAD3 cooperativity (Milliat et al., 2008).

12. Mutation of the p53-binding sites in the PAI-1 promoter inhibits γ-radiation-induced PAI-1 transcription and attenuates the dual γ-radiation + TGF-β1 synergy (Hageman et al., 2005).

13. γ-radiation did not induce PAI-1 expression in p53-null cells; p53 expression rescue largely restored the PAI-1 response to γ-radiation + TGF-β1 co-stimulation (Hageman et al., 2005).

14. p53 knockdown mitigates radiation-dependent PAI-1 expression (Szołtysek et al., 2018).

15. Overexpression of the Δ133p53α isoform of p53, which lacks the two transactivation domains, inhibits expression of the p53-inducible genes p21, IGFBP7, and PAI-1 (Fujita, 2019).