Soluble αβ-tubulins reversibly sequester TTC5 to regulate tubulin mRNA decay.

Microtubules, built from heterodimers of α- and β-tubulins, control cell shape, mediate intracellular transport, and power cell division. The concentration of αβ-tubulins is tightly controlled through a posttranscriptional mechanism involving selective and regulated degradation of tubulin-encoding mRNAs. Degradation is initiated by TTC5, which recognizes tubulin-synthesizing ribosomes and recruits downstream effectors to trigger mRNA deadenylation.

Mechanism of ribosome-associated mRNA degradation during tubulin autoregulation.

Microtubules play crucial roles in cellular architecture, intracellular transport, and mitosis. The availability of free tubulin subunits affects polymerization dynamics and microtubule function. When cells sense excess free tubulin, they trigger degradation of the encoding mRNAs, which requires recognition of the nascent polypeptide by the tubulin-specific ribosome-binding factor TTC5.

Lethal Poisoning of Cancer Cells by Respiratory Chain Inhibition plus Dimethyl α-Ketoglutarate.

Inhibition of oxidative phosphorylation (OXPHOS) by 1-cyclopropyl-4-(4-[(5-methyl-3-(3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl]pyridin-2-yl)piperazine (BAY87-2243, abbreviated as B87), a complex I inhibitor, fails to kill human cancer cells in vitro. Driven by this consideration, we attempted to identify agents that engage in synthetically lethal interactions with B87. Here, we report that dimethyl α-ketoglutarate (DMKG), a cell-permeable precursor of α-ketoglutarate that lacks toxicity on its own, kills cancer cells when combined with B87 or other inhibitors of OXPHOS.

Cytosolic Hsp90α and its mitochondrial isoform Trap1 are differentially required in a breast cancer model.

The Hsp90 family of molecular chaperones includes the cytosolic isoforms Hsp90α and Hsp90β, and the mitochondrial isoform Trap1. Hsp90α/β support a large number of client proteins in the cytoplasm and the nucleus whereas Trap1 regulates oxidative phosphorylation in mitochondria. Many of the associated proteins and cellular processes are relevant to cancer, and there is ample pharmacological and genetic evidence to support the idea that Hsp90α/β and Trap1 are required for tumorigenesis.

Unusual Suspects in the Twilight Zone Between the Hsp90 Interactome and Carcinogenesis.

The molecular chaperone Hsp90 has attracted a lot of interest in cancer research ever since cancer cells were found to be more sensitive to Hsp90 inhibition than normal cells. Why that is has remained a matter of debate and is still unclear. In addition to increased Hsp90 dependence for some mutant cancer proteins and modifications of the Hsp90 machinery itself, a number of other characteristics of cancer cells probably contribute to this phenomenon; these include aneuploidy and overall increased numbers and levels of defective and mutant proteins, which all contribute to perturbed proteostasis.

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis.

TRAP1 (TNF receptor-associated protein), a member of the HSP90 chaperone family, is found predominantly in mitochondria. TRAP1 is broadly considered to be an anticancer molecular target. However, current inhibitors cannot distinguish between HSP90 and TRAP1, making their utility as probes of TRAP1-specific function questionable.