p53-dependent and p53-independent activation of autophagy by ARF Academic Article uri icon

Overview

MeSH Major

  • Autophagy
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53

abstract

  • The ARF tumor suppressor is a crucial component of the cellular response to hyperproliferative signals, including oncogene activation, and functions by inducing a p53-dependent cell growth arrest and apoptosis program. It has recently been reported that the ARF mRNA can produce a smARF isoform that lacks the NH(2)-terminal region required for p53 activation. Overexpression of this isoform can induce autophagy, a cellular process characterized by the formation of cytoplasmic vesicles and the digestion of cellular content, independently of p53. However, the level of this isoform is extremely low in cells, and it remains unclear whether the predominant form of ARF, the full-length protein, is able to activate autophagy. Here, we show that full-length ARF can induce autophagy in 293T cells where p53 is inactivated by viral proteins, and, notably, expression of the NH(2)-terminal region alone, which is required for nucleolar localization, is sufficient for autophagy activation, independently of p53. Given the reported ability of p53 to induce autophagy, we also investigated the role of p53 in ARF-mediated autophagy induction. We found that full-length ARF expression induces p53 activation and promotes autophagy in a p53-positive cell line, and that ARF-mediated autophagy can be abrogated, at least in part, by RNAi-mediated knockdown of p53 in this cellular context. Thus, our findings modify the current view regarding the mechanism of autophagy induction by ARF and suggest an important role for autophagy in tumor suppression via full-length ARF in both p53-dependent and p53-independent manners, depending on cellular context.

publication date

  • January 15, 2008

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3737745

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-07-2069

PubMed ID

  • 18199527

Additional Document Info

start page

  • 352

end page

  • 7

volume

  • 68

number

  • 2