Distinct Structural Domains within C19ORF5 Support Association with Stabilized Microtubules and Mitochondrial Aggregation and Genome Destruction
- 15 May 2005
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 65 (10), 4191-4201
- https://doi.org/10.1158/0008-5472.can-04-3865
Abstract
C19ORF5 is a sequence homologue of microtubule-associated proteins MAP1A/MAP1B of unknown function, except for its association with mitochondria-associated proteins and the paclitaxel-like microtubule stabilizer and candidate tumor suppressor RASSF1A. Here, we show that when overexpressed in mammalian cells the recombinant 393–amino acid residue COOH terminus of C19ORF5 (C19ORF5C) exhibited four types of distribution patterns proportional to expression level. Although normally distributed throughout the cytosol without microtubular association, C19ORF5C specifically accumulated on stabilized microtubules in paclitaxel-treated cells and interacted directly with paclitaxel-stabilized microtubules in vitro. The native 113-kDa full-length C19ORF5 and a shorter 56-kDa form similarly associated with stabilized microtubules in liver cells and stabilized microtubules from their lysates. As C19ORF5 accumulated, it appeared on mitochondria and progressively induced distinct perinuclear aggregates of mitochondria. C19ORF5 overlapped with cytochrome c–deficient mitochondria with reduced membrane potential. Mitochondrial aggregation resulted in gross degradation of DNA, a cell death–related process we refer to as mitochondrial aggregation and genome destruction (MAGD). Deletion mutagenesis revealed that the C19ORF5 hyperstabilized microtubule-binding domain resides in a highly basic sequence of <100 residues, whereas the MAGD activity resides further downstream in a distinct 25-residue sequence (F967-A991). Our results suggest that C19ORF5 mediates communication between the microtubular cytoskeleton and mitochondria in control of cell death and defective genome destruction through distinct bifunctional structural domains. The accumulation of C19ORF5 and resultant MAGD signaled by hyperstabilized microtubules may be involved in the tumor suppression activity of RASSF1A, a natural microtubule stabilizer and interaction partner with C19ORF5, and the taxoid drug family.Keywords
This publication has 49 references indexed in Scilit:
- Specificity of the Methylation-Suppressed A Isoform of Candidate Tumor Suppressor RASSF1 for Microtubule Hyperstabilization Is Determined by Cell Death Inducer C19ORF5Cancer Research, 2005
- Tumor suppressor RASSF1A is a microtubule-binding protein that stabilizes microtubules and induces G2/M arrestOncogene, 2004
- A Role for the RASSF1A Tumor Suppressor in the Regulation of Tubulin Polymerization and Genomic StabilityCancer Research, 2004
- RASSF1A Interacts with Microtubule-Associated Proteins and Modulates Microtubule DynamicsCancer Research, 2004
- Destructive cycles: the role of genomic instability and adaptation in carcinogenesisCarcinogenesis: Integrative Cancer Research, 2004
- Microtubule‐associated protein 1B function during normal development, regeneration, and pathological conditions in the nervous systemJournal of Neurobiology, 2003
- Aberrant Tau Phosphorylation by Glycogen Synthase Kinase-3β and JNK3 Induces Oligomeric Tau Fibrils in COS-7 CellsPublished by Elsevier BV ,2002
- Novel Features of the Light Chain of Microtubule-associated Protein MAP1B: Microtubule Stabilization, Self Interaction, Actin Filament Binding, and Regulation by the Heavy ChainThe Journal of cell biology, 1998
- The 55-kDa Tumor Necrosis Factor Receptor Induces Clustering of Mitochondria through Its Membrane-proximal RegionPublished by Elsevier BV ,1998
- Movement of Bax from the Cytosol to Mitochondria during ApoptosisThe Journal of cell biology, 1997