A short mitochondrial form of p19ARF induces autophagy and caspase-independent cell death.
The tumor suppressor functions of p19(ARF) have been attributed to its ability to induce cell cycle arrest or apoptosis by activating p53 and regulating ribosome biogenesis. Here we describe another cellular function of p19(ARF), involving a short isoform (smARF, short mitochondrial ARF) that localizes to a Proteinase K-resistant compartment of the mitochondria. smARF is a product of internal initiation of translation at Met45, which lacks the nucleolar functional domains. The human p14(ARF) mRNA likewise produces a shorter isoform. smARF is maintained at low levels via proteasome-mediated degradation, but it increases in response to viral and cellular oncogenes. Ectopic expression of smARF reduces mitochondrial membrane potential (DeltaPsim) without causing cytochrome c release or caspase activation. The dissipation of DeltaPsim does not depend on p53 or Bcl-2 family members. smARF induces massive autophagy and caspase-independent cell death that can be partially rescued by knocking down ATG5 or Beclin-1, suggesting a different prodeath function for this short isoform.
Reef
Sharon
S
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Zalckvar
Einat
E
Shifman
Ohad
O
Bialik
Shani
S
Sabanay
Helena
H
Oren
Moshe
M
Kimchi
Adi
A
D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006367:HeLa Cells; D006801:Humans; D008564:Membrane Potentials; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D020169:Caspases; D046988:Proteasome Endopeptidase Complex