학술논문
The anti-apoptotic proteins NAF-1 and iASPP interact to drive apoptosis in cancer cells.
Document Type
Academic Journal
Author
Iosub-Amir A; Institute of Chemistry , The Hebrew University of Jerusalem , Edmond J. Safra Campus at Givat Ram , Jerusalem 91904 , Israel . Email: assaf.friedler@mail.huji.ac.il.; Bai F; Center for Theoretical Biological Physics , Department of Physics , Rice University , Houston , TX 77005 , USA . Email: jonuchic@rice.edu.; Sohn YS; The Alexander Silberman Institute of Life Science , The Hebrew University of Jerusalem , Edmond J. Safra Campus at Givat Ram , Jerusalem 91904 , Israel . Email: rachel@mail.huji.ac.il.; Song L; Department of Biological Sciences , University of North Texas , Denton , TX 76203 , USA.; Tamir S; The Alexander Silberman Institute of Life Science , The Hebrew University of Jerusalem , Edmond J. Safra Campus at Givat Ram , Jerusalem 91904 , Israel . Email: rachel@mail.huji.ac.il.; Marjault HB; The Alexander Silberman Institute of Life Science , The Hebrew University of Jerusalem , Edmond J. Safra Campus at Givat Ram , Jerusalem 91904 , Israel . Email: rachel@mail.huji.ac.il.; Mayer G; Institute of Chemistry , The Hebrew University of Jerusalem , Edmond J. Safra Campus at Givat Ram , Jerusalem 91904 , Israel . Email: assaf.friedler@mail.huji.ac.il.; Karmi O; The Alexander Silberman Institute of Life Science , The Hebrew University of Jerusalem , Edmond J. Safra Campus at Givat Ram , Jerusalem 91904 , Israel . Email: rachel@mail.huji.ac.il.; Jennings PA; Department of Chemistry & Biochemistry , University of California at San Diego , La Jolla , CA 92093 , USA.; Mittler R; Department of Surgery , University of Missouri School of Medicine , Christopher S. Bond Life Sciences Center , University of Missouri , 1201 Rollins St , Columbia , MO 65201 , USA.; Onuchic JN; Center for Theoretical Biological Physics , Department of Physics , Rice University , Houston , TX 77005 , USA . Email: jonuchic@rice.edu.; Friedler A; Institute of Chemistry , The Hebrew University of Jerusalem , Edmond J. Safra Campus at Givat Ram , Jerusalem 91904 , Israel . Email: assaf.friedler@mail.huji.ac.il.; Nechushtai R; The Alexander Silberman Institute of Life Science , The Hebrew University of Jerusalem , Edmond J. Safra Campus at Givat Ram , Jerusalem 91904 , Israel . Email: rachel@mail.huji.ac.il.
Source
Publisher: Royal Society of Chemistry Country of Publication: England NLM ID: 101545951 Publication Model: eCollection Cited Medium: Print ISSN: 2041-6520 (Print) Linking ISSN: 20416520 NLM ISO Abbreviation: Chem Sci Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
2041-6520
Abstract
Suppression of apoptosis is a key Hallmark of cancer cells, and reactivation of apoptosis is a major avenue for cancer therapy. We reveal an interaction between the two anti-apoptotic proteins iASPP and NAF-1, which are overexpressed in many types of cancer cells and tumors. iASPP is an inhibitory member of the ASPP protein family, whereas NAF-1 belongs to the NEET 2Fe-2S protein family. We show that the two proteins are stimulated to interact in cells during apoptosis. Using peptide array screening and computational methods we mapped the interaction interfaces of both proteins to residues 764-778 of iASPP that bind to a surface groove of NAF-1. A peptide corresponding to the iASPP 764-780 sequence stabilized the NAF-1 cluster, inhibited NAF-1 interaction with iASPP, and inhibited staurosporine-induced apoptosis activation in human breast cancer, as well as in PC-3 prostate cancer cells in which p53 is inactive. The iASPP 764-780 IC 50 value for inhibition of cell death in breast cancer cells was 13 ± 1 μM. The level of cell death inhibition by iASPP 764-780 was altered in breast cancer cells expressing different levels and/or variants of NAF-1, indicating that the peptide activity is associated with NAF-1 function. We propose that the interaction between iASPP and NAF-1 is required for apoptosis activation in cancer cells. This interaction uncovers a new layer in the highly complex regulation of cell death in cancer cells and opens new avenues of exploration into the development of novel anticancer drugs that reactivate apoptosis in malignant tumors.