It has been proposed that the copy number of mitochondria DNA (mtDNA) per cell reflects gene–environment interactions between unknown hereditary factors and exposures affecting levels of oxidative stress. However, whether copy number of mtDNA could be a risk predictor of oxidative stress-related human cancers, such as breast cancer, remains to be determined. To explore the role of mtDNA copy number in breast cancer etiology, we analyzed mtDNA copy number in whole blood from 103 patients with breast cancer and 103 matched control subjects and examined in relation to endogenous antioxidants. Case patients with breast cancer had a statistically significantly higher mtDNA copy number than control subjects (median: 1.29 vs. 0.80, P < 0.01). High mtDNA copy number (above the median in controls) was associated with a statistically significantly increased risk of breast cancer, compared with low copy number (Odds ratio (OR) = 4.67, 95% CI: 2.45–8.92), with a statistically significant dose–response relationship in trend analysis (P < 0.01). Moreover, mtDNA copy number was significantly inversely associated with several important endogenous oxidants and antioxidants in blood in either the cases (total glutathione, CuZn-SOD activity and myeloperoxidase (MPO)) or the controls (catalase (CAT) activity). These results suggest the mtDNA copy number could be associated with risk of breast cancer, perhaps through an oxidative stress mechanism.
The motile activities of the small, single-headed class I myosins (myosin I) from the lower eukaryotes Acanthamoeba and Dictyostelium are activated by phosphorylation of a single serine or threonine residue in the head domain of the heavy chain. Recently, we purified a myosin I heavy chain kinase (MIHCK) from Dictyostelium based on its ability to activate the Dictyostelium myosin ID isozyme (Lee, S.-F., and Cô té , G. P. (1995) J. Biol. Chem. 270, 11776 -11782). The complete sequence of the Dictyostelium MIHCK has now been determined, revealing a protein of 98 kDa that is composed of an amino-terminal domain rich in proline, glutamine, and serine, a putative Cdc42/Rac binding motif, and a carboxyl-terminal kinase catalytic domain. MIHCK shares significant sequence identity with the Saccharomyces cerevisiae Ste20p kinase and the mammalian p21-activated kinase. Gel overlay assays and affinity chromatography experiments showed that MIHCK interacted with GTP␥S (guanosine 5-3-O-(thiotriphosphate))-labeled Cdc42 and Rac1 but not RhoA. In the presence of GTP␥S-Rac1 MIHCK autophosphorylation increased from 1 to 9 mol of phosphate/mol, and the rate of Dictyostelium myosin ID phosphorylation was stimulated 10-fold. MIHCK may therefore provide a direct link between Cdc42/Rac signaling pathways and motile processes driven by myosin I molecules.The class I myosins (myosin I) are small, single-headed, non-filament-forming myosins present in organisms ranging from protozoans such as Acanthamoeba and Dictyostelium to mammalian cells (1-3). Myosin I molecules are comprised of a 110 -140-kDa heavy chain and one or more light chains, with the amino-terminal ϳ80 kDa of the heavy chain forming a motor domain, or head, that displays actin-activated MgATPase activity and drives actin-based motile processes. The carboxyl-terminal portion of the myosin I heavy chain forms a globular tail domain that incorporates an acidic phospholipidbinding site and, in some isozymes, a nucleotide-insensitive actin filament-binding site, and a Src homology 3 (SH3) 1 domain. Detailed biochemical studies on the Acanthamoeba myosin I isozymes have shown that phosphorylation of a single site in the head region of the heavy chain is required for these myosins to express maximal actin-activated MgATPase activity, to contract actin gels, and to move actin filaments (4 -6).Evidence is available to indicate that at least two of the five Dictyostelium myosin I isozymes (myosin IB and ID) are regulated in an analogous manner (7-9). Recently, we isolated a Dictyostelium MIHCK based on its ability to activate the Dictyostelium myosin ID isozyme (9). We now report the complete cDNA sequence encoding the Dictyostelium MIHCK and show that it is a member of a protein kinase family that includes the Saccharomyces cerevisiae Ste20p and the mammalian p21-activated kinase (PAK). Members of the PAK kinase family bind to, and in some cases are activated by, Cdc42 and Rac (10 -12), two members of the Rho group of p21 Ras-related GTP-binding proteins (13). Evidence is presente...
Dictyostelium PakB, previously termed myosin I heavy chain kinase, is a member of the p21-activated kinase (PAK) family. Two-hybrid assays showed that PakB interacts with Dictyostelium Rac1a/b/c, RacA (a RhoBTB protein), RacB, RacC, and RacF1. Wild-type PakB displayed a cytosolic distribution with a modest enrichment at the leading edge of migrating cells and at macropinocytic and phagocytic cups, sites consistent with a role in activating myosin I. PakB fused at the N terminus to green fluorescent protein was proteolyzed in cells, resulting in removal of the catalytic domain. C-terminal truncated PakB and activated PakB lacking the p21-binding domain strongly localized to the cell cortex, to macropinocytic cups, to the posterior of migrating cells, and to the cleavage furrow of dividing cells. These data indicate that in its open, active state, the N terminus of PakB forms a tight association with cortical actin filaments. PakB-null cells displayed no significant behavioral defects, but cells expressing activated PakB were unable to complete cytokinesis when grown in suspension and exhibited increased rates of phagocytosis and pinocytosis. INTRODUCTIONMembers of the p21-activated kinase (PAK) family are key regulators of the actin cytoskeleton and cell motility in organisms ranging from yeast to mammals (Bokoch, 2003). PAKs are characterized by the presence of two conserved domains: a p21-binding domain (PBD) and a C-terminal Ser/Thr protein kinase catalytic domain. The PBD mediates interactions with active Cdc42 and Rac GTPases and encompasses an autoinhibitory sequence that potently suppresses the activity of the catalytic domain. The binding of GTPCdc42/Rac to the PBD disrupts the autoinhibitory interaction, permitting a series of autophosphorylation events that maximize kinase activity.Studies on Dictyostelium discoideum have provided valuable insights into the signaling pathways that regulate cell polarization and chemotaxis (Merlot and Firtel, 2003). To date, three Dictyostelium PAKs have been identified: PakA (Chung and Firtel, 1999), PakB (Lee et al., 1996), and PakC (GenBank accession no. AF277804). The three PAK isoforms share between 50 and 70% sequence identity within the PBD and catalytic domains but exhibit no homology outside of these regions. Loss of PakA produces cytokinesis defects in cells grown in suspension culture and prevents cells from suppressing lateral pseudopod extension or from properly retracting the cell posterior during chemotaxis (Chung and Firtel, 1999;Chung et al., 2001). These authors conclude that PakA, which localizes to the posterior of migrating cells, functions to promote the assembly of myosin II into bipolar filaments. In a second study, PakA-null cells were found to display no detectable defects with respect to locomotion or cytokinesis (Muller-Taubenberger et al., 2002).PakB was initially identified through its ability to phosphorylate and activate MyoD, a single-headed type I myosin (Lee and Côté, 1995;Lee et al., 1996). PakB was originally called myosin I heavy cha...
BackgroundWaterpipe tobacco smoking is increasing in popularity especially among young adults. This spread could be related to limited knowledge of the negative health effects of waterpipe smoking. In this study, prevalence, social acceptance, and awareness of waterpipe smoking were examined among dental university students.MethodsThis is a cross-sectional survey study, where a self-administered questionnaire was completed by a sample of dental university students in Jordan.ResultsStudents (n = 547) reported current tobacco use of 54.3% for males versus 11.1% for females (P <0.005). Among current smokers, 3.5% used only cigarettes (22.0% males, 2.3% females), 12.6% used only waterpipe (36.6% males, 88.6% females), and 6.9% used both (41.5% males, 9.1% females). Approximately, 70% of males and 42.5% of females who used waterpipe reported smoking mostly at a café. Nearly half of the females reported that they smoke at home in the presence of parents. Among participants, 33.3% of males and 62.5% of females reported indifferent parents’ reaction regarding their waterpipe smoking. Approximately one third of students agreed with the statement that waterpipe smoking is less harmful to oral health than cigarette smoking. About 50-70% of students agreed that waterpipe smoking causes halitosis, delays wound healing time, is associated with dental implant failure, and increases the risk of dental decay.ConclusionsIn this sample, waterpipe tobacco smoking was more common than cigarette smoking among dental students, especially females. This could be an implication of social acceptance of waterpipe leading to its predominance, and thus, the gradual replacement of cigarette smoking with waterpipe smoking. Additionally, dental students’ awareness about the harms of waterpipe is not optimal, and steps are needed to ensure providing such knowledge to students.
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