14-3-3 mediated regulation of the tumor suppressor protein, RASSF1A

Haya Abu Ghazaleh, Renfred S Chow, Sheryl L Choo, Diana Pham, Jamie D Olesen, Russell X Wong, Christina Onyskiw, Shairaz Baksh

    Research output: Contribution to journalArticlepeer-review

    21 Citations (Scopus)

    Abstract

    Death receptor-dependent apoptosis is an important mechanism of growth control. It has been demonstrated that Ras association domain family protein 1A (RASSF1A) is a tumor suppressor protein involved in death receptor-dependent apoptosis. However, it is unclear how RASSF1A-mediated cell death is initiated. We have now detailed 14-3-3 dependent regulation of RASSF1A-mediated cell death. We demonstrate that basal association of RASSF1A with 14-3-3 was lost following stimulation with tumor necrosis factor alpha (TNFalpha) or TNFalpha related apoptosis inducing ligand (TRAIL). Subsequent to the loss of 14-3-3 association, RASSF1A associated with modulator of apoptosis (MOAP-1) followed by death receptor association with either TNFalpha receptor 1 (TNF-R1) or TRAIL receptor 1 (TRAIL-R1). 14-3-3 association required basal phosphorylation by the serine/threonine kinase, glycogen synthase kinase 3beta (GSK-3beta), on serine 175, 178, and 179. Mutation of these critical serines resulted in the loss of 14-3-3 association and earlier recruitment of RASSF1A to MOAP-1, TNF-R1, and TRAIL-R1. Furthermore, stable cells containing a triple serine mutant of RASSF1A [serine (S) 175 to alanine (A) [S175A], S178A, and S179A] resulted in increased basal cell death, enhanced Annexin V staining and enhanced cleavage of poly (ADP-ribose) polymerase (PARP) following TNFalpha stimulation when compared to stable cells containing wild type RASSF1A. RASSF1A-mediated cell death is, therefore, tightly controlled by 14-3-3 association.

    Original languageEnglish
    Pages (from-to)117-27
    Number of pages11
    JournalAPOPTOSIS
    Volume15
    Issue number2
    DOIs
    Publication statusPublished - Feb 2010

    Keywords

    • 14-3-3 Proteins
    • Adaptor Proteins, Signal Transducing
    • Amino Acid Sequence
    • Apoptosis Regulatory Proteins
    • Binding Sites
    • Cell Death
    • Cell Line, Tumor
    • Glycogen Synthase Kinase 3
    • Glycogen Synthase Kinase 3 beta
    • Humans
    • Kinetics
    • Models, Biological
    • Molecular Sequence Data
    • Mutant Proteins
    • Phosphorylation
    • Protein Binding
    • Receptors, Death Domain
    • Receptors, TNF-Related Apoptosis-Inducing Ligand
    • Receptors, Tumor Necrosis Factor, Type I
    • Tumor Suppressor Proteins
    • Journal Article
    • Research Support, Non-U.S. Gov't

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