p66Shc is involved in promoting HIF-1α accumulation and cell death in hypoxic T cells

Fabio Carraro, Annalisa Pucci, Michela Pellegrini, Pier Giuseppe Pelicci, Cosima T. Baldari, Antonella Naldini

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Hypoxia results in adaptationally appropriate alterations of gene expression through the activation of hypoxia-inducible factor (HIF)-1 to overcome any shortage of oxygen. Peripheral blood mononuclear cells may be exposed to low oxygen tensions for different times as they migrate between blood and various tissues. We and others have previously shown that T-cell adaptation to hypoxia is characterized by a modulation of cytokine expression and an inhibition of T-cell activation. We have recently demonstrated that the adaptor protein p66Shc negatively regulates T-cell activation and survival. We here show that hypoxia enhances HIF-1α accumulation and vascular endothelial growth factor production in T cells. Hypoxic T cells expressed high levels of p21 WAF1/CIP1, of the pro-apoptotic molecules BNIP3, a classic HIF target gene, and BAX, as well as low levels of the anti-apoptotic molecule BCLx1, associated with an induction of cell death. We found out that hypoxic T cells expressed p66Shc. Furthermore, using T-cell transfectants expressing p66Shc, as well as T cells derived from mice p66Shc-/-, we defined a role of p66Shc in T-cell responses to hypoxia. Of interest, hypoxic p66Shc-positive transfectants expressed higher level of HIF-1α than negative controls. Thus, p66Shc may play an important role in downstream hypoxic signaling, involving HIF-1α protein accumulation and cell death in T lymphocytes.

Original languageEnglish
Pages (from-to)439-447
Number of pages9
JournalJournal of Cellular Physiology
Issue number2
Publication statusPublished - May 2007

ASJC Scopus subject areas

  • Cell Biology
  • Clinical Biochemistry
  • Physiology


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