Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1

Oncogene. 2002 Jun 20;21(27):4212-9. doi: 10.1038/sj.onc.1205610.


Human astrocytic brain tumors select for mutations in the p53 tumor suppressor gene early in malignant progression. p53 is activated upon various kinds of cellular stress leading to apoptosis or cell cycle arrest, but is also implicated in complex biological processes such as inhibition of angiogenesis and metastasis. In an effort to shed light on consequences mediated by p53 inactivation in gliomas, we established the Tet-On system for p53 in the LN-Z308 glioblastoma cell line. The macrophage inhibitory cytokine-1 (MIC-1) gene was identified as a most prominent p53 target gene upon gene expression profiling. Oxygen deprivation, an important cellular stress, revealed MIC-1 as an anoxia responsive gene in glioblastoma cell lines. MIC-1 up-regulation by anoxia is mediated through an alternative, p53 and hypoxia inducible factor 1 (HIF-1) independent pathway. Furthermore, ectopic expression of MIC-1 in LN-Z308 cell line completely abolished its inherent tumorigenicity in nude mice, while proliferation in vitro was not affected. In the present experimental model MIC-1 may exert its anti-tumorigenic properties via a paracrine mechanism mediated by host cells in vivo. Taken together, these data suggest that MIC-1 is an important downstream mediator of p53 function, while acting itself as an intercessor of cellular stress signaling and exerting anti-tumorigenic activities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology*
  • Cell Hypoxia / genetics
  • Cytokines / biosynthesis*
  • Cytokines / genetics
  • DNA-Binding Proteins / physiology*
  • Dexamethasone / pharmacology
  • Doxycycline / pharmacology
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Genes, p53
  • Glioblastoma / genetics
  • Glioblastoma / metabolism
  • Glioblastoma / pathology*
  • Growth Differentiation Factor 15
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology
  • Neoplasm Transplantation
  • Nuclear Proteins / physiology*
  • Oxygen / pharmacology*
  • Recombinant Fusion Proteins / physiology
  • Signal Transduction
  • Transcription Factors*
  • Transplantation, Heterologous
  • Tumor Suppressor Protein p53 / physiology*


  • Cytokines
  • DNA-Binding Proteins
  • GDF15 protein, human
  • Gdf15 protein, mouse
  • Growth Differentiation Factor 15
  • HIF1A protein, human
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Neoplasm Proteins
  • Nuclear Proteins
  • Recombinant Fusion Proteins
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Dexamethasone
  • Doxycycline
  • Oxygen