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The novel p53 target Tumor Necrosis Factor-α-Induced Protein 8 variant 2 is increased in human cancers and can offset p53-dependent tumor suppression

Thursday, September 17, 2015 — Poster Session II

12:00 p.m. – 1:30 p.m.
FAES Terrace
NIEHS
CANCER-19

* FARE Award Winner

Authors

  • JM Lowe
  • T Nguyen
  • MA Resnick
  • SA Grimm
  • KA Gabor
  • SD Peddada
  • CW Anderson
  • D Menendez
  • MB Fessler

Abstract

Tumor Necrosis Factor-α-Induced Protein 8 (TNFAIP8) is a stress-response gene that has been associated with cancer, but no studies have differentiated among nor defined the regulation or function of any of its several recently described expression variants. We found that TNFAIP8 variant 2 (v2) is overexpressed in multiple human cancers and cancer cell lines, whereas other variants are commonly downregulated in cancer (v1) or minimally expressed in cancer or normal tissue (v3-v6). Silencing v2 in cancer cells induces p53-independent DNA replication stalling, as well as widespread binding of p53 to and induction of target genes, and p53-dependent cell cycle arrest, senescence, and DNA damage sensitization. Cell cycle arrest and senescence induced by v2 silencing both require p53-dependent induction of p21. In response to the chemotherapeutic agent doxorubicin, p53 regulates v2 through binding to an intragenic enhancer, together indicating that p53 and v2 engage in complex reciprocal regulation. We propose that TNFAIP8 v2 can promote human cancer through p53-independent mechanisms as well as by broadly repressing p53 function, in essence offsetting p53-dependent tumor suppression.

Category: Cancer Biology