Mitochondria have emerged as central regulators of apoptosis. Here, we show that TID1, a human homolog of the Drosophila tumor suppressor lethal (2) tumorous imaginal discs, l(2)tid, encodes two mitochondrial matrix proteins, designated hTid-1 L and hTid-1 S . These splice variants are both highly conserved members of the DnaJ family of proteins, which regulate the activity of and confer substrate specificity to Hsp70 proteins. Both hTid-1 L and hTid-1 S coimmunoprecipitate with mitochondrial Hsp70. Expression of hTid-1 L or hTid-1 S have no apparent capacity to induce apoptosis but have opposing effects on apoptosis induced by exogenous stimuli. Expression of hTid-1 L increases apoptosis induced by both the DNA-damaging agent mitomycin c and tumor necrosis factor ␣. This activity is J domain-dependent, because a J domain mutant of hTid-1 L can dominantly suppress apoptosis. In sharp contrast, expression of hTid-1 S suppresses apoptosis, whereas expression of a J domain mutant of hTid-1 S increases apoptosis. Hence, we propose that TID1 gene products act to positively and negatively modulate apoptotic signal transduction or effector structures within the mitochondrial matrix.The Drosophila l(2)tid gene has been classified as a tumor suppressor and encodes Tid56, a 56-kDa protein that is processed to a 50-kDa mitochondrial localized protein (1-3). Null mutants of Tid56 exhibit a lethal phenotype in which cells of the imaginal discs fail to differentiate and grow into lethal tumors. TID1, a human homolog of l(2)tid, encodes hTid-1, a 52-kDa protein with strong homology to Tid56 (4).hTid-1 and Tid56 are members of the DnaJ family of proteins. DnaJ proteins act as cochaperones and specificity factors for DnaK proteins and their eukaryotic homologs, the Hsp70 family (5-8). This protein family is characterized by a J domain, a highly conserved tetrahelical domain that binds to Hsp70 chaperones and activates their ATPase activity. The canonical J domain protein, DnaJ, was cloned from Escherichia coli as a mutant that cannot support the replication of bacteriophage (9, 10). DnaJ/Hsp70 systems are involved in protein folding (11), protein degradation, assembly and disassembly of multiprotein complexes (7), and translocation of proteins across membranes (12).The hyperproliferative phenotype of l(2)tid mutant embryos suggests that the Tid56 protein is involved in regulation of cell growth or death. Given the mitochondrial localization of Tid56 and the important role of mitochondria in regulating apoptosis (13,14), the tumorous imaginal discs phenotype may reflect a failure of imaginal disc cells to properly integrate stimuli of cell death and survival. Several mitochondrial activities have been implicated in transducing, amplifying, and repressing apoptotic signals, including the release of cytochrome c and ApoptosisInducing Factor from the mitochondrial intermembrane space, the production of reactive oxygen species, and the loss of inner membrane potential. In addition, mitochondrial localization is important for ...

We have cloned hTid-1, a human homolog of the Drosophila tumor suppressor protein Tid56, by virtue of its ability to form complexes with the human papillomavirus E7 oncoprotein. The carboxyl terminal cysteine-rich metal binding domain of E7 is the major determinant for interaction with hTid-1. The carboxyl terminus of E7 is essential for the functional and structural integrity of E7 and has previously been shown to function as a multimerization domain. The hTid-1 protein is a member of the DnaJ-family of chaperones. Its mRNA is widely expressed in human tissues, including the HPV-18-positive cervical carcinoma cell line HeLa and human genital keratinocytes, the normal host cells of the HPVs. The hTid-1 gene has been mapped to the short arm of chromosome 16. The large tumor antigens of polyomaviruses encode functional J-domains that are important for viral replication as well as cellular transformation. The ability of HPV E7 to interact with a cellular DnaJ protein suggests that these two viral oncoproteins may target common regulatory pathways through J-domains.

The hepatitis B virus (HBV) surface antigen (HBsAG) is encoded by the S gene under the regulation of a promoter in the pre‐S1 region. The S gene promoter does not contain a ‘TATA’ box‐like sequence, but there is a sequence resembling, in part, the late promoter of Simian virus 40 (SV40). In an attempt to study the regulation of the S gene promoter we looked for cellular proteins which bind to this region. We report here that a nuclear protein is tightly bound to the HBV genome at a position approximately 190 bases upstream from the S gene promoter. Evidence is provided to show that (a) this nuclear protein is the nuclear factor I (NF‐I) that was previously found to be bound to the inverted terminal repeat of the adenovirus (Ad) DNA and to enhance Ad DNA replication in vitro and (b) this NF‐I binding site is required for optimal activity of the S gene promoter.

Antimicrobial resistance is an emerging public-health threat. Studies of the relationship between antibiotic use and resistance, as well as surveillance programmes, examine changes in the proportion of isolates that are resistant. Although proportions are helpful to the clinician prescribing empirical therapy, proportion-based analyses can be misleading to the public-health professional as they can yield biased estimates. Proportions do not adequately reflect the burden of resistance, a measure often of interest in public health. A more appropriate measure of this burden is the rate of isolation of resistant organisms, that is, the absolute number of resistant isolates in a population over time.