Nucleolar stress is an early response to myocardial damage involving nucleolar proteins nucleostemin and nucleophosmin

Daniele Avitabile, Brandi Bailey, Christopher T. Cottage, Balaji Sundararaman, Anya Joyo, Michael McGregor, Natalie Gude, Silvia Truffa, Aryan Zarrabi, Mathias Konstandin, Mohsin Khan, Sadia Mohsin, Mirko Völkers, Haruhiro Toko, Matt Mason, Zhaokang Cheng, Shabana Din, Roberto Alvarez, Kimberlee Fischer, Mark A. Sussman

Research output: Contribution to journalArticle

Abstract

Nucleolar stress, characterized by loss of nucleolar integrity, has not been described in the cardiac context. In addition to ribosome biogenesis, nucleoli are critical for control of cell proliferation and stress responses. Our group previously demonstrated induction of the nucleolar protein nucleostemin (NS) in response to cardiac pathological insult. NS interacts with nucleophosmin (NPM), a marker of nucleolar stress with cytoprotective properties. The dynamic behavior of NS and NPM reveal that nucleolar disruption is an early event associated with stress response in cardiac cells. Rapid translocation of NS and NPM to the nucleoplasm and suppression of new preribosomal RNA synthesis occurs in both neonatal rat cardiomyocytes (NRCM) and cardiac progenitor cells (CPC) upon exposure to doxorubicin or actinomycin D. Silencing of NS significantly increases cell death resulting from doxorubicin treatment in CPC, whereas NPM knockdown alone induces cell death. Overexpression of either NS or NPM significantly decreases caspase 8 activity in cultured cardiomyocytes challenged with doxorubicin. The presence of altered nucleolar structures resulting from myocardial infarction in mice supports the model of nucleolar stress as a general response to pathological injury. Collectively, these findings serve as the initial description of myocardial nucleolar stress and establish the postulate that nucleoli acts as sensors of stress, regulating the cellular response to pathological insults.

Original languageEnglish
Pages (from-to)6145-6150
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number15
DOIs
Publication statusPublished - Apr 12 2011

Keywords

  • Hypertrophy
  • Hypoxia
  • Nucleolus
  • rRNA

ASJC Scopus subject areas

  • General

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