Many types of cancer cells constitutively express major molecular chaperones at high levels. Recent findings demonstrate that specific depletion of individual chaperones, including various members of the Hsp70 family, small heat shock proteins, or VCP/p97, leads to activation of p53 pathway and subsequently triggers cellular senescence. Here, we discuss a possibility that in cancer cells high levels of chaperones serve to keep the p53 signaling under control, thus allowing cancer cells to evade the default senescence and form tumors.

Lumenal ecto-nucleoside tri-and di-phosphohydrolases (ENTPDases) of the secretory pathway of eukaryotes hydrolyze nucleoside diphosphates resulting from glycosyltransferase-mediated reactions, yielding nucleoside monophosphates. The latter are weaker inhibitors of glycosyltransferases than the former and are also antiporters for the transport of nucleotide sugars from the cytosol to the endoplasmic reticulum (ER) and Golgi apparatus (GA) lumen. Here we describe the presence of two cation-dependent nucleotide phosphohydrolase activities in membranes of Caenorhabditis elegans: one, UDA-1, is a UDP/GDPase encoded by the gene uda-1, whereas the other is an apyrase encoded by the gene ntp-1. UDA-1 shares significant amino acid sequence similarity to yeast GA Gda1p and mammalian UDP/GDPases and has a lumenal active site in vesicles displaying an intermediate density between those of the ER and GA when expressed in S. cerevisiae. NTP-1 expressed in COS-7 cells appeared to localize to the GA. The transcript of uda-1 but not those of two other C. elegans ENTPDase mRNAs (ntp-1 and mig-23) was induced up to 3.5-fold by high temperature, tunicamycin, and ethanol. The same effectors triggered the unfolded protein response as shown by the induction of expression of green fluorescent protein under the control of the BiP chaperone promoter and the UDP-glucose:glycoprotein glucosyltransferase. Up-regulation of uda-1 did not occur in ire-1-deficient mutants, demonstrating the role of this ER stress sensor in this event. We hypothesize that up-regulation of uda-1 favors hydrolysis of the glucosyltransferase inhibitory product UDP to UMP, and that the latter product then exits the lumen of the ER or pre-GA compartment in a coupled exchange with the entry of UDP-glucose, thereby further relieving ER stress by favoring protein re-glycosylation.The occurrence of the eukaryotic endomembrane system has brought forth a need for a mechanism to coordinate the metabolic flux of nucleotides, nucleotide sugars, and nucleotide sulfate between the cytosol and the lumen of secretory organelles. E-type ATPases play an important role in this function. They have been conserved through evolution with their catalytic site in the ecto-position, facing the outer surface of the plasma membrane or its topological equivalent, the lumen of intracellular organelles such as the endoplasmic reticulum (ER), 1 Golgi apparatus (GA), and lysosomes/vacuoles. These enzymes, members of the ecto-nucleoside triphosphate diphosphohydrolase (ENTPDase) family, hydrolyze nucleoside tri-and/or diphosphates in the presence of cations and share, at the amino acid sequence level, five conserved motifs called apyrase-conserved regions (ACRs) (1).Extracellular nucleotides such as ATP and ADP are intercellular signaling molecules in virtually every tissue where, modulated by ecto-apyrases, they participate in a broad range of biological processes such as the regulation of immune responses (2) and modulation of signaling by neuronal cells (3). Specifically, mammalian ENTPDase1/CD...

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