Research article summary (published 8 Sep 2009):

A role for nuclear translocation of tripeptidyl-peptidase II in reactive oxygen species-dependent DNA damage responses.

Full Abstract

Responses to DNA damage are influenced by cellular metabolism through the continuous production of reactive oxygen species (ROS), of which most are by-products of mitochondrial respiration. ROS have a strong influence on signaling pathways during responses to DNA damage, by relatively unclear mechanisms. Previous reports have shown conflicting data on a possible role for tripeptidyl-peptidase II (TPPII), a large cytosolic peptidase, within the DNA damage response. Here we show that TPPII translocated into the nucleus in a p160-ROCK-dependent fashion in response to gamma-irradiation, and that nuclear expression of TPPII was present in most gamma-irradiated transformed cell lines. We used a panel of nine cell lines of diverse tissue origin, including four lymphoma cell lines (T, B and Hodgkins lymphoma), a melanoma, a sarcoma, a colon and two breast carcinomas, where seven out of nine cell lines showed nuclear TPPII expression after gamma-irradiation. Further, this required cellular production of ROS; treatment with either N-acetyl-Cysteine (anti-oxidant) or Rotenone (inhibitor of mitochondrial respiration) inhibited nuclear accumulation of TPPII. The local density of cells was important for nuclear accumulation of TPPII at early time-points following gamma-irradiation (at 1-4h), indicating a bystander effect. Further, we showed that the peptide-based inhibitor Z-Gly-Leu-Ala-OH, but not its analogue Z-Gly-(D)-Leu-Ala-OH, excluded TPPII from the nucleus. This correlated with reduced nuclear expression of p53 as well as caspase-3 and -9 activation in gamma-irradiated lymphoma cells. Our data suggest a role for TPPII in ROS-dependent DNA damage responses, through alteration of its localization from the cytosol into the nucleus.

Author information

Author/s: Preta, Giulio (G); de Klark, Rainier (R); Glas, Rickard (R);

Affiliation: Center for Molecular Medicine (CMM), Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 171 76 Stockholm, Sweden.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun), published in United States. (Language: eng)

Reference: 2009-Nov; vol 389 (issue 4) : pp 575-9

Dates: Created 2009/10/14; Completed 2009/11/02;

PMID: 19747897, status: MEDLINE (last retrieval date: 11/2/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Active Transport, Cell Nucleus - drug effects; radiation effects Animals Apoptosis Cell Line, Tumor Cell Nucleus - enzymology DNA Damage

Gamma Rays Humans Mice Reactive Oxygen Species - metabolism Serine Endopeptidases - metabolism Tumor Suppressor Protein p53 - metabolism

Associated Chemicals: Reactive Oxygen Species (0) ; Tumor Suppressor Protein p53 (0) ; tripeptidyl-peptidase 2 (EC 3.4.14.10) ; Serine Endopeptidases (EC 3.4.21.-)

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