title: Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in a p53-dependent manner.
abstract: Chemotherapy and radiation, the two most common cancer therapies, exert their anticancer effects by causing damage to cellular DNA. However, systemic treatment damages DNA not only in cancer, but also in healthy cells, resulting in the progression of serious side effects and limiting efficacy of the treatment. Interestingly, in response to DNA damage, p53 seems to play an opposite role in normal and in the majority of cancer cells-wild-type p53 mediates apoptosis in healthy tissues, attributing to the side effects, whereas mutant p53 often is responsible for acquired cancer resistance to the treatment. Here, we show that leucine zipper-containing ARF-binding protein (LZAP) binds and stabilizes p53. LZAP depletion eliminates p53 protein independently of its mutation status, subsequently protecting wild-type p53 cells from DNA damage-induced cell death, while rendering cells expressing mutant p53 more sensitive to the treatment. In human non-small-cell lung cancer, LZAP levels correlated with p53 levels, suggesting that loss of LZAP may represent a novel mechanism of p53 inactivation in human cancer. Our studies establish LZAP as a p53 regulator and p53-dependent determinative of cell fate in response to DNA damaging treatment.
authors.affiliation: Division of Otolaryngology, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Wamsley
authors.affiliation: Division of Otolaryngology, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: C
authors.initials: C
authors.lastname: Gary
authors.affiliation: Division of Otolaryngology, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: A
authors.initials: A
authors.lastname: Biktasova
authors.affiliation: Division of Otolaryngology, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hajek
authors.affiliation: Division of Otolaryngology, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: G
authors.initials: G
authors.lastname: Bellinger
authors.affiliation: Division of Otolaryngology, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: R
authors.initials: R
authors.lastname: Virk
authors.affiliation: Division of Otolaryngology, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.|Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: N
authors.initials: N
authors.lastname: Issaeva
authors.affiliation: Division of Otolaryngology, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.|Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.|Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: W G
authors.initials: WG
authors.lastname: Yarbrough