WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy
Department of Neurobiology; Waddell Lab
Medical Subject Headings
Amino Acid Sequence; Autophagy; Glutathione Transferase; Hela Cells; Humans; Molecular Sequence Data; Neoplasm Proteins; Neoplasms; Phylogeny; Protein Binding; Receptors, Steroid; Recombinant Fusion Proteins; Sequence Homology, Amino Acid; *Starvation
Neuroscience and Neurobiology
WD-repeat proteins are regulatory beta-propeller platforms that enable the assembly of multiprotein complexes. Here, we report the functional and bioinformatic analysis of human WD-repeat protein Interacting with PhosphoInosides (WIPI)-1alpha (WIPI49/Atg18), a member of a novel WD-repeat protein family with autophagic capacity in Saccharomyces cerevisiae and Caenorhabditis elegans, recently identified as phospholipid-binding effectors. Our phylogenetic analysis divides the WIPI protein family into two paralogous groups that fold into 7-bladed beta-propellers. Structural modeling identified two evolutionary conserved interaction sites in WIPI propellers, one of which may bind phospholipids. Human WIPI-1alpha has LXXLL signature motifs for nuclear receptor interactions and binds androgen and estrogen receptors in vitro. Strikingly, human WIPI genes were found aberrantly expressed in a variety of matched tumor tissues including kidney, pancreatic and skin cancer. We found that endogenous hWIPI-1 protein colocalizes in part with the autophagosomal marker LC3 at punctate cytoplasmic structures in human melanoma cells. In addition, hWIPI-1 accumulated in large vesicular and cup-shaped structures in the cytoplasm when autophagy was induced by amino-acid deprivation. These cytoplasmic formations were blocked by wortmannin, a classic inhibitor of PI-3 kinase-mediated autophagy. Our data suggest that WIPI proteins share an evolutionary conserved function in autophagy and that autophagic capacity may be compromised in human cancers.
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Citation: Oncogene. 2004 Dec 16;23(58):9314-25. Link to article on publisher's site
Proikas-Cezanne, Tassula; Waddell, Scott; Gaugel, Anja; Frickey, Tancred; Lupas, Andrei; and Nordheim, Alfred, "WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy" (2004). Neurobiology Publications and Presentations. Paper 74.