PHAPI, CAS, and Hsp70 Promote Apoptosome Formation by Preventing Apaf-1 Aggregation and Enhancing Nucleotide Exchange on Apaf-1

Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Molecular cell (Impact Factor: 14.46). 05/2008; 30(2):239-47. DOI: 10.1016/j.molcel.2008.03.014
Source: PubMed

ABSTRACT During apoptosis, cytochrome c is released from mitochondria to the cytosol, where it binds Apaf-1. The Apaf-1/cytochrome c complex then oligomerizes either into heptameric caspase-9-activating apoptosome, which subsequently activates caspase-3 and caspase-7, or bigger inactive aggregates, depending on the availability of nucleotide dATP/ATP. A tumor suppressor protein, PHAPI, enhances caspase-9 activation by promoting apoptosome formation through an unknown mechanism. We report here the identification of cellular apoptosis susceptibility protein (CAS) and heat shock protein 70 (Hsp70) as mediators of PHAPI activity. PHAPI, CAS, and Hsp70 function together to accelerate nucleotide exchange on Apaf-1 and prevent inactive Apaf-1/cytochrome c aggregation. CAS expression is induced by multiple apoptotic stimuli including UV irradiation. Knockdown of CAS by RNA interference (RNAi) in cells attenuates apoptosis induced by UV light and causes endogenous Apaf-1 to form aggregates. These studies indicated that PHAPI, CAS, and Hsp70 play an important regulatory role during apoptosis.

Download full-text


Available from: Fenghe Du, Jun 24, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The process of muscle cell differentiation into myotubes, termed myogenesis, depends on a complex coordination of myogenic factors, many of which are regulated post-transcriptionally. HuR, an mRNA-binding protein, is responsible for regulating the expression of several such myogenic factors by stabilizing their mRNAs. The critical role for HuR in myogenesis also involves the nucleocytoplasmic shuttling ability of this protein. Indeed, in order to perform its stabilizing functions, HuR must accumulate in the cytoplasm. This requires its dissociation from the import factor Transportin 2 (TRN2) which is actually caused by the cleavage of a portion of cytoplasmic HuR. In this review, we describe the roles of HuR during myogenesis, and the mechanisms regulating its cytoplasmic accumulation. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.
    Biochimica et Biophysica Acta 02/2011; 1813(9):1663-7. DOI:10.1016/j.bbamcr.2011.01.036 · 4.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Heat shock proteins (HSPs) play a role in the homeostasis, apoptosis regulation and the maintenance of the various other physiological processes. Aging is accompanied by a decrease in the resistance to environmental stress, while mitochondria are primary targets in the process of aging, their expression decreasing with age. Mitochondrion also plays a significant role in the process of spermatogenesis. HSPs have been shown to be involved in apoptosis with some of acting as apoptotic inhibitors and are involved in cytoprotection. In this review we discuss the roles of Hsp 27, 60, 70, and 90 in aging and male infertility and have concluded that these particular HSPs can be used as a molecular markers for mitochondrially-mediated apoptosis, aging and male infertility.
    12/2014; 32(3)(31st):2287-4208. DOI:10.5534/wjmh.2014.32.3.123
  • Source