The Inhibitors of Apoptosis (IAPs) and Their Emerging Role in Cancer

Oncogene. 1998 Dec 24;17(25):3247-59. doi: 10.1038/sj.onc.1202569.

Abstract

The inhibitor of apoptosis protein family has been characterized over the past 5 years, initially in baculovirus and more recently in metazoans. The IAPs are a widely expressed gene family of apoptotic inhibitors from both phylogenic and physiologic points of view. The diversity of triggers against which the IAPs suppress apoptosis is greater than that observed for any other family of apoptotic inhibitors including the bcl-2 family. The central mechanisms of IAP apoptotic suppression appear to be through direct caspase and pro-caspase inhibition (primarily caspase 3 and 7) and modulation of and by the transcription factor NF-kappaB. Although evidence for a direct oncogenic role for the IAPs has yet to be delineated, a number of lines of evidence point towards this class of protein playing a role in oncogenesis. The strongest evidence for IAP involvement in cancer is seen in the IAP called survivin. Although not observed in adult differentiated tissue, survivin is present in most transformed cell lines and cancers tested to date. Survivin has been shown to inhibit caspase directly and apoptosis in general, moreover survivin protein levels correlate inversely with 5 year survival rates in colorectal cancer. Recent data has also implicated survivin in cell cycle control. The second line of evidence for IAP involvement in cancer comes from their emerging role as mediators and regulators of the anti-apoptotic activity of v-Rel and NF-kappaB transcription factor families. The IAPs have been shown to be induced by NF-kappaB or v-Rel in multiple cell lines and conversely, HIAP1 and HIAP2 have been shown to activate NF-kappaB possibly forming a positive feed-back loop. Overall a picture consistent with an IAP role in tumour progression rather than tumour initiation is emerging making the IAPs an attractive therapeutic target.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis*
  • Caspases / drug effects
  • Caspases / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins*
  • Molecular Sequence Data
  • NF-kappa B / physiology
  • Neoplasm Proteins
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Oncogene Proteins v-rel
  • Protein Biosynthesis
  • Protein-Tyrosine Kinases
  • Proteins / metabolism
  • Proteins / physiology*
  • Retroviridae Proteins, Oncogenic / physiology
  • Sequence Homology, Amino Acid
  • Survivin
  • Transcription Factors
  • Ubiquitin-Protein Ligases
  • Viral Proteins / physiology
  • Zinc Fingers

Substances

  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • NF-kappa B
  • Neoplasm Proteins
  • Oncogene Proteins v-rel
  • Proteins
  • Retroviridae Proteins, Oncogenic
  • Survivin
  • Transcription Factors
  • Viral Proteins
  • inhibitor of apoptosis, Nucleopolyhedrovirus
  • BIRC2 protein, human
  • Ubiquitin-Protein Ligases
  • Protein-Tyrosine Kinases
  • Caspases