ZFP1

ZFP1 (human PITA) is a KRAB-type C2H2 zinc-finger transcriptional repressor that functions as a stress-responsive, selective negative regulator of p53-mediated metabolic control (PMID:29467382). PITA physically interacts with p53 and specifically suppresses transcription of the p53 glycolysis-regulating target gene TIGAR, while sparing other p53 targets such as SCO2; consistent with this, PITA transgenic mice show increased PFK1 activity and elevated glycolytic rate (PMID:29467382). Under glucose starvation, ATM kinase-mediated phosphorylation of PITA drives its dissociation from p53, permitting p53 activation and TIGAR induction that inhibits aerobic glycolysis, thereby coupling metabolic stress sensing to p53 transcriptional output (PMID:29467382). The protein's domain architecture—seven C2H2 zinc fingers with Krüppel-like organization—was defined in the mouse ortholog (PMID:2574853). Beyond this p53/TIGAR axis and the structural characterization, no further mechanistic detail has been characterized in the available corpus.

1. 1989 Medium

   Established the molecular identity and domain architecture of the gene, defining it as a Krüppel-related C2H2 zinc-finger protein with potential DNA-binding/transcription-factor function.

   Evidence cDNA cloning, sequence analysis, Northern blot expression profiling and chromosomal mapping of mouse Zfp1

   PMID:2574853

   Open questions at the time

   • Structural assignment of zinc fingers was inferred from sequence without functional mutagenesis
   • No DNA target or binding specificity defined
   • No transcriptional or biochemical activity demonstrated
2. 2018 High

   Resolved the functional role of human PITA/ZFP1 as a p53-binding repressor that selectively silences TIGAR to promote glycolysis, and defined ATM phosphorylation as the switch that releases this repression under glucose starvation.

   Evidence Reciprocal Co-IP, luciferase reporter assays, transgenic mouse metabolic phenotyping (PFK1 activity, glycolytic rate), glucose starvation and ATM inhibitor experiments, and PITA depletion in colorectal cancer cells

   PMID:29467382

   Open questions at the time

   • Direct DNA binding of PITA at the TIGAR locus versus indirect repression via p53 not fully distinguished
   • Specific ATM phosphosite(s) on PITA not mapped
   • Basis for selectivity toward TIGAR over other p53 targets such as SCO2 unexplained

• How PITA achieves promoter selectivity among p53 targets and whether it engages chromatin or co-repressor machinery via its KRAB/zinc-finger domains remains unresolved.
• No structural model of the PITA-p53 interface
• No genome-wide DNA-binding map
• Co-repressor partners of the KRAB domain not identified