Biomedical subjects

J M Peters

Publications and source records attributed to J M Peters.

At least 91 records · Page 5Linked to original sources

PubMed1999

CYP2E1 is not involved in early alcohol-induced liver injury.

The continuous intragastric enteral feeding protocol in the rat was a major development in alcohol-induced liver injury (ALI) research. Much of what has been learned to date involves inhibitors or nutritional manipulations that may not be specific. Knockout technology avoids these potential problems. Therefore, we used long-term intragastric cannulation in mice to study early ALI. Reactive oxygen species are involved in mechanisms of early ALI; however, their key source remains unclear. Cytochrome P-450 (CYP)2E1 is induced predominantly in hepatocytes by ethanol and could be one source of reactive oxygen species leading to liver injury. We aimed to determine if CYP2E1 was involved in ALI by adapting the enteral alcohol (EA) feeding model to CYP2E1 knockout (-/-) mice. Female CYP2E1 wild-type (+/+) or -/- mice were given a high-fat liquid diet with either ethanol or isocaloric maltose-dextrin as control continuously for 4 wk. All mice gained weight steadily over 4 wk, and there were no significant differences between groups. There were also no differences in ethanol elimination rates between CYP2E1 +/+ and -/- mice after acute ethanol administration to naive mice or mice receiving EA for 4 wk. However, EA stimulated rates 1.4-fold in both groups. EA elevated serum aspartate aminotransferase levels threefold to similar levels over control in both CYP2E1 +/+ and -/- mice. Liver histology was normal in control groups. In contrast, mice given ethanol developed mild steatosis, slight inflammation, and necrosis; however, there were no differences between the CYP2E1 +/+ and -/- groups. Chronic EA induced other CYP families (CYP3A, CYP2A12, CYP1A, and CYP2B) to the same extent in CYP2E1 +/+ and -/- mice. Furthermore, POBN radical adducts were also similar in both groups. Data presented here are consistent with the hypothesis that oxidants from CYP2E1 play only a small role in mechanisms of early ALI in mice. Moreover, this new mouse model illustrates the utility of knockout technology in ALI research.

Animals↗

PubMed1999

A study of twelve Southern California communities with differing levels and types of air pollution. I. Prevalence of respiratory morbidity.

To study possible chronic respiratory effects of air pollutants, we initiated a 10-yr prospective cohort study of Southern California children, with a study design focused on four pollutants: ozone, particulate matter, acids, and nitrogen dioxide (NO2). Twelve demographically similar communities were selected on the basis of historic monitoring information to represent extremes of exposure to one or more pollutants. In each community, about 150 public school students in grade 4, 75 in grade 7, and 75 in grade 10 were enrolled through their classrooms. Informed consent and written responses to surveys about students' lifetime residential histories, historic and current health status, residential characteristics, and physical activity were obtained with the help of the parents. In the first testing season, 3,676 students returned questionnaires. We confirmed associations previously reported between respiratory morbidity prevalence and the presence of personal, demographic, and residential risk factors. Rates of respiratory illness were higher for males, those living in houses with pets, pests, mildew, and water damage, those whose parents had asthma, and those living in houses with smokers. Wheeze prevalence was positively associated with levels of both acid (odds ratio [OR] = 1.45; 95% confidence interval [CI], 1.14-1.83) and NO2 (OR = 1.54; 95% CI, 1.08-2.19) in boys. We conclude, based on this cross-sectional assessment of questionnaire responses, that current levels of ambient air pollution in Southern California may be associated with effects on schoolchildren's respiratory morbidity as assessed by questionnaire.

Acids↗

PubMed1999

A study of twelve Southern California communities with differing levels and types of air pollution. II. Effects on pulmonary function.

To study the possible chronic respiratory effects of air pollutants, we designed and initiated a 10-yr prospective study of Southern California public schoolchildren living in 12 communities with different levels and profiles of air pollution. The design of the study, exposure assessment methods, and survey methods and results related to respiratory symptoms and conditions are described in the accompanying paper. Pulmonary function tests were completed on 3,293 subjects. We evaluated cross-sectionally the effects of air pollution exposures based on data collected in 1986-1990 by existing monitoring stations and data collected by our study team in 1994. Expected relationships were seen between demographic, physical, and other environmental factors and pulmonary function values. When the data were stratified by sex, an association was seen between pollution levels and lower pulmonary function in female subjects, with the associations being stronger for the 1994 exposure data than the 1986-1990 data. After adjustment, PM10, PM2.5, and NO2 were each significantly associated with lower FVC, FEV1, and maximal midexpiratory flow (MMEF); acid vapor with lower FVC, FEV1, peak expiratory flow rate (PEFR), and MMEF; and O3 with lower PEFR and MMEF. Effects were generally larger in those girls spending more time outdoors. Stepwise regression of adjusted pulmonary function values for girls in the 12 communities showed that NO2 was most strongly associated with lower FVC (r = -0.74, p < 0.01), PM2.5 with FEV1 (r = -0.72, p < 0.01), O3 with PEFR (r = -0.75, p < 0.005), and PM2.5 with MMEF (r = -0.80, p < 0.005). There was a statistically significant association between ozone exposure and decreased FVC and FEV1 in girls with asthma. For boys, significant associations were seen between peak O3 exposures and lower FVC and FEV1, but only in those spending more time outdoors. These findings underline the importance of follow-up of this cohort.

Acids↗

PubMed1999

Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting.

Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor known as peroxisome proliferator-activated receptor alpha (PPARalpha) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPARalpha may be involved in the transcriptional response to fasting. To investigate this possibility, PPARalpha-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wild-type mice. PPARalpha-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPARalpha-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevated plasma free fatty acid levels, indicating a dramatic inhibition of fatty acid uptake and oxidation. It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPARalpha mRNA is induced during fasting in wild-type mice. The data indicate that PPARalpha plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARalpha stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues.

Acyl-CoA Dehydrogenase↗

PubMed1999

Air pollution and bronchitic symptoms in Southern California children with asthma.

The association of air pollution with the prevalence of chronic lower respiratory tract symptoms among children with a history of asthma or related symptoms was examined in a cross-sectional study. Parents of a total of 3,676 fourth, seventh, and tenth graders from classrooms in 12 communities in Southern California completed questionnaires that characterized the children's histories of respiratory illness and associated risk factors. The prevalences of bronchitis, chronic phlegm, and chronic cough were investigated among children with a history of asthma, wheeze without diagnosed asthma, and neither wheeze nor asthma. Average ambient annual exposure to ozone, particulate matter (PM(10) and PM(2.5); [less than/equal to] 10 microm and < 2.5 microm in aerodynamic diameter, respectively), acid vapor, and nitrogen dioxide (NO(2)) was estimated from monitoring stations in each community. Positive associations between air pollution and bronchitis and phlegm were observed only among children with asthma. As PM(10) increased across communities, there was a corresponding increase in the risk per interquartile range of bronchitis [odds ratio (OR) 1.4/19 microg/m(3); 95% confidence interval (CI), 1.1-1.8). Increased prevalence of phlegm was significantly associated with increasing exposure to all ambient pollutants except ozone. The strongest association was for NO(2), based on relative risk per interquartile range in the 12 communities (OR 2.7/24 ppb; CI, 1.4-5.3). The results suggest that children with a prior diagnosis of asthma are more likely to develop persistent lower respiratory tract symptoms when exposed to air pollution in Southern California.

Adolescent↗

PubMed1999

Modulation of cytochrome P-450 gene expression in endotoxemic mice is tissue specific and peroxisome proliferator-activated receptor-alpha dependent.

Administration of the bacterial endotoxin lipopolysaccharide (LPS) causes induction of cytochrome P-450 (CYP) 4A mRNAs in rat liver and kidney. Because induction of the CYP4A subfamily by chemicals requires peroxisome proliferator-activated receptor-alpha (PPARalpha), we determined whether CYP4A induction by LPS also requires PPARalpha by comparing the responses of PPARalpha-null (-/-) and wild-type (+/+) mice. Renal expression of CYP4A10, CYP4A14, and acyl-CoA oxidase was induced by LPS treatment in (+/+) mice, and these effects were absent in the (-/-) mice. In contrast, hepatic expression of CYP4A10 was down-regulated in the (+/+) animals, and no significant induction of acyl-CoA oxidase or CYP4A14 was detected in liver. Expression of the peroxisomal bifunctional enzyme was not significantly affected by LPS treatment. These results indicate that PPARalpha is activated in mouse kidney after LPS treatment and that this leads to modulation of some PPARalpha-regulated genes. However, the species and tissue specificity of these effects suggest that inflammatory pathways may modulate the induction via PPARalpha. Mice pair fed with LPS-treated mice showed no induction of renal CYP4A10 or CYP4A14, indicating that renal CYP4A induction during endotoxemia is not due to hypophagia. Down-regulation of CYP2A5, CYP2C29, and CYP3A11 by LPS was attenuated or blocked in the (-/-) mice, suggesting a role for PPARalpha in CYP down-regulation as well. Finally, we found that clofibrate caused an acute induction of two hepatic acute-phase mRNAs that was only partially dependent on PPARalpha.

Animals↗

PubMed1999

Residential magnetic fields predicted from wiring configurations: I. Exposure model.

A physically based model for residential magnetic fields from electric transmission and distribution wiring was developed to reanalyze the Los Angeles study of childhood leukemia by London et al. For this exposure model, magnetic field measurements were fitted to a function of wire configuration attributes that was derived from a multipole expansion of the Law of Biot and Savart. The model parameters were determined by nonlinear regression techniques, using wiring data, distances, and the geometric mean of the ELF magnetic field magnitude from 24-h bedroom measurements taken at 288 homes during the epidemiologic study. The best fit to the measurement data was obtained with separate models for the two major utilities serving Los Angeles County. This model's predictions produced a correlation of 0.40 with the measured fields, an improvement on the 0.27 correlation obtained with the Wertheimer-Leeper (WL) wire code. For the leukemia risk analysis in a companion paper, the regression model predicts exposures to the 24-h geometric mean of the ELF magnetic fields in Los Angeles homes where only wiring data and distances have been obtained. Since these input parameters for the exposure model usually do not change for many years, the predicted magnetic fields will be stable over long time periods, just like the WL code. If the geometric mean is not the exposure metric associated with cancer, this regression technique could be used to estimate long-term exposures to temporal variability metrics and other characteristics of the ELF magnetic field which may be cancer risk factors.

Algorithms↗

PubMed1999

Residential magnetic fields predicted from wiring configurations: II. Relationships To childhood leukemia.

Case-control data on childhood leukemia in Los Angeles County were reanalyzed with residential magnetic fields predicted from the wiring configurations of nearby transmission and distribution lines. As described in a companion paper, the 24-h means of the magnetic field's magnitude in subjects' homes were predicted by a physically based regression model that had been fitted to 24-h measurements and wiring data. In addition, magnetic field exposures were adjusted for the most likely form of exposure assessment errors: classic errors for the 24-h measurements and Berkson errors for the predictions from wire configurations. Although the measured fields had no association with childhood leukemia (P for trend=.88), the risks were significant for predicted magnetic fields above 1.25 mG (odds ratio=2.00, 95% confidence interval=1.03-3.89), and a significant dose-response was seen (P for trend=.02). When exposures were determined by a combination of predictions and measurements that corrects for errors, the odds ratio (odd ratio=2.19, 95% confidence interval=1.12-4.31) and the trend (p =.007) showed somewhat greater significance. These findings support the hypothesis that magnetic fields from electrical lines are causally related to childhood leukemia but that this association has been inconsistent among epidemiologic studies due to different types of exposure assessment error. In these data, the leukemia risks from a child's residential magnetic field exposure appears to be better assessed by wire configurations than by 24-h area measurements. However, the predicted fields only partially account for the effect of the Wertheimer-Leeper wire code in a multivariate analysis and do not completely explain why these wire codes have been so often associated with childhood leukemia. The most plausible explanation for our findings is that the causal factor is another magnetic field exposure metric correlated to both wire code and the field's time-averaged magnitude.

Algorithms↗

PubMed1998

Mechanism of action of the nongenotoxic peroxisome proliferators: role of the peroxisome proliferator-activator receptor alpha.

Peroxisome proliferators are a diverse group of chemicals that include several therapeutically used drugs (e.g., hypolipidemic agents), plasticizers and organic solvents used in the chemical industry, herbicides, and naturally occurring hormones. As the name implies, peroxisome proliferators cause an increase in the number and size of peroxisomes in the liver, kidney, and heart tissue of susceptible species, such as rats and mice. Long-term administration of peroxisome proliferators can cause liver cancer in these animals, a response that has been the central issue of research on peroxisome proliferators for many years. Peroxisome proliferators are representative of the class of nongenotoxic carcinogens that cause cancer through mechanisms that do not involve direct DNA damage. The fact that humans are frequently exposed to these agents makes them of particular concern to government regulatory agencies responsible for assuring human safety. Whether frequent exposure to peroxisome proliferators represents a hazard to humans is unknown; however, increased cancer risk has not been shown to be associated with long-term therapeutic administration of the hypolipidemic drugs gemfibrozil, fenofibrate, and clofibrate. To make sound judgments regarding the safety of peroxisome proliferators, the validity of extrapolating results from rodent bioassays to humans must be based on the agents' mechanism of action and species differences in biologic activity and carcinogenicity. The peroxisome proliferator-activated receptor alpha (PPARalpha), a member of the nuclear receptor superfamily, has been found to mediate the activity of peroxisome proliferators in mice. Gene-knockout mice lacking PPARalpha are refractory to peroxisome proliferation and peroxisome proliferator-induced changes in gene expression. Furthermore, PPARalpha-null mice are resistant to hepatocarcinogenesis when fed a diet containing a potent nongenotoxic carcinogen WY-14,643. Recent studies have revealed that humans have considerably lower levels of PPARalpha in liver than rodents, and this difference may, in part, explain the species differences in the carcinogenic response to peroxisome proliferators.

Animals↗

PubMed1998

Dispersal of first "workers" in social wasps: causes and implications of an alternative reproductive strategy.

Many "workers" in north temperate colonies of the eusocial paper wasp Polistes fuscatus disappear within a few days of eclosion. We provide evidence that these females are pursuing an alternative reproductive strategy, i.e., dispersing to overwinter and become nest foundresses the following spring, instead of helping to rear brood on their natal nests. A female is most likely to stay and help at the natal nest (i.e., least likely to disperse) when it is among the first workers to emerge and when it emerges on a nest with more pupae (even though worker-brood relatedness tends to be lower in such colonies). The latter cause may result from the fact that pupae-laden nests are especially likely to survive, and thus any direct or indirect reproductive payoffs for staying and working are less likely to be lost. Disappearing females are significantly smaller than predicted if dispersal tendency was independent of body size (emergence order-controlled), suggesting that the females likely to be most effective at challenging for reproductive rights within the natal colony (i.e., the largest females) are also most likely to stay. Thus, early dispersal is conditional on a female's emergence order, the maturity of its natal nest, and its body size. Finally, we present evidence that foundresses may actively limit the sizes of first-emerging females, perhaps to decrease the probability that the latter can effectively challenge foundresses for reproductive rights. The degree to which foundresses limit the size of first-emerging females accords well with the predictions of the theory of staying incentives.

Animals↗

PubMed1998

Activation of the human anaphase-promoting complex by proteins of the CDC20/Fizzy family.

The initiation of anaphase and exit from mitosis depend on the activation of the cyclosome/anaphase-promoting complex (APC) that ubiquitinates regulatory proteins such as anaphase inhibitors and mitotic cyclins [1-4]. Genetic experiments have demonstrated that two related WD40-repeat proteins--called Cdc20p and Hct1p/Cdh1p in budding yeast and Fizzy and Fizzy-related in Drosophila--are essential for APC--dependent proteolysis [5-11]. Human orthologs of these proteins--hCDC20/p55CDC [12] and hCDH1--have recently been found to associate with APC in a cell-cycle-dependent manner [13,14]. Here, we show that the amount of hCDC20 and hCDH1 bound to APC correlates with a high ubiquitination activity of APC and that binding of recombinant hCDC20 and hCDH1 can activate APC in vitro. Our results suggest that the association between hCDH1 and APC is regulated by post-translational mechanisms, whereas the amount of hCDC20 bound to APC may in addition be controlled by hCDC20 synthesis and destruction [15]. The temporally distinct association of hCDC20 and hCDH1 with APC suggests that these proteins are, respectively, mitosis-specific and G1-specific activating subunits of APC.

Anaphase-Promoting Complex-Cyclosome↗

PubMed1998

Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner.

Regulation of gene expression of three putative long-chain fatty acid transport proteins, fatty acid translocase (FAT), mitochondrial aspartate aminotransferase (mAspAT), and fatty acid transport protein (FATP), by drugs that activate peroxisome proliferator-activated receptor (PPAR) alpha and gamma were studied using normal and obese mice and rat hepatoma cells. FAT mRNA was induced in liver and intestine of normal mice and in hepatoma cells to various extents only by PPARalpha-activating drugs. FATP mRNA was similarly induced in liver, but to a lesser extent in intestine. The induction time course in the liver was slower for FAT and FATP mRNA than that of an mRNA encoding a peroxisomal enzyme. An obligatory role of PPARalpha in hepatic FAT and FATP induction was demonstrated, since an increase in these mRNAs was not observed in PPARalpha-null mice. Levels of mAspAT mRNA were higher in liver and intestine of mice treated with peroxisome proliferators, while levels in hepatoma cells were similar regardless of treatment. In white adipose tissue of KKAy obese mice, thiazolidinedione PPARgamma activators (pioglitazone and troglitazone) induced FAT and FATP more efficiently than the PPARalpha activator, clofibrate. This effect was absent in brown adipose tissue. Under the same conditions, levels of mAspAT mRNA did not change significantly in these tissues. In conclusion, tissue-specific expression of FAT and FATP genes involves both PPARalpha and -gamma. Our data suggest that among the three putative long-chain fatty acid transporters, FAT and FATP appear to have physiological roles. Thus, peroxisome proliferators not only influence the metabolism of intracellular fatty acids but also cellular uptake, which is likely to be an important regulatory step in lipid homeostasis.

Adipates↗

PubMed1998

Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha).

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the steroid/nuclear receptor superfamily and mediates the biological and toxicological effects of peroxisome proliferators. To determine the physiological role of PPARalpha in fatty acid metabolism, levels of peroxisomal and mitochondrial fatty acid metabolizing enzymes were determined in the PPARalpha null mouse. Constitutive liver beta-oxidation of the long chain fatty acid, palmitic acid, was lower in the PPARalpha null mice as compared with wild type mice, indicating defective mitochondrial fatty acid catabolism. In contrast, constitutive oxidation of the very long chain fatty acid, lignoceric acid, was not different between wild type and PPARalpha null mice, suggesting that constitutive expression of enzymes involved in peroxisomal beta-oxidation is independent of PPARalpha. Indeed, the PPARalpha null mice had normal levels of the peroxisomal acyl-CoA oxidase, bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase), and thiolase but lower constitutive expression of the D-type bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase). Several mitochondrial fatty acid metabolizing enzymes including very long chain acyl-CoA dehydrogenase, long chain acyl-CoA dehydrogenase, short chain-specific 3-ketoacyl-CoA thiolase, and long chain acyl-CoA synthetase are also expressed at lower levels in the untreated PPARalpha null mice, whereas other fatty acid metabolizing enzymes were not different between the untreated null mice and wild type mice. A lower constitutive expression of mRNAs encoding these enzymes was also found, suggesting that the effect was due to altered gene expression. In wild type mice, both peroxisomal and mitochondrial enzymes were induced by the peroxisome proliferator Wy-14,643; induction was not observed in the PPARalpha null animals. These data indicate that PPARalpha modulates constitutive expression of genes encoding several mitochondrial fatty acid-catabolizing enzymes in addition to mediating inducible mitochondrial and peroxisomal fatty acid beta-oxidation, thus establishing a role for the receptor in fatty acid homeostasis.

17-Hydroxysteroid Dehydrogenases↗

PubMed1998

Identification of a cullin homology region in a subunit of the anaphase-promoting complex.

The anaphase-promoting complex is composed of eight protein subunits, including BimE (APC1), CDC27 (APC3), CDC16 (APC6), and CDC23 (APC8). The remaining four human APC subunits, APC2, APC4, APC5, and APC7, as well as human CDC23, were cloned. APC7 contains multiple copies of the tetratrico peptide repeat, similar to CDC16, CDC23, and CDC27. Whereas APC4 and APC5 share no similarity to proteins of known function, APC2 contains a region that is similar to a sequence in cullins, a family of proteins implicated in the ubiquitination of G1 phase cyclins and cyclin-dependent kinase inhibitors. The APC2 gene is essential in Saccharomyces cerevisiae, and apc2 mutants arrest at metaphase and are defective in the degradation of Pds1p. APC2 and cullins may be distantly related members of a ubiquitin ligase family that targets cell cycle regulators for degradation.

Amino Acid Sequence↗

PubMed1998

Ancient conservation of trinucleotide microsatellite loci in polistine wasps.

Microsatellites have proven to be very useful genetic markers for studies of kinship, parentage, and gene mapping. If microsatellites are conserved among species, then those developed for one species can be used on related species, which would save the time and effort of developing new loci. We evaluated conservation of 27 trinucleotide loci that were derived from 2 species of Polistes wasps in cross-species applications on 27 species chosen from the major lineages of the Vespidae, which diverged as much as 144 million years ago. We further investigated cross-species polymorphism levels for 18 of the loci. There was a clear relationship between cladistic distance and both conservation of the priming sites and heterozygosity. However the loci derived from P. bellicosus were much more widely conserved and polymorphic than were those derived from P. annularis. The disparity in cross-species utility between these sets of loci means that caution should be used in generalizing from conservation rates derived from single species. We found no relationship between locus conservation or heterozygosity and GC content of flanks, repeat motif, repeat length, or heterozygosity in the original species, which suggests that generalizations from other studies reporting such patterns are premature.

Animals↗

PubMed1998

SCF and APC: the Yin and Yang of cell cycle regulated proteolysis.

Progression through the cell cycle requires the activity of two ubiquitination complexes, the Skp1-cullin-F-box-protein complex (SCF) and the anaphase-promoting complex/cyclosome (APC). Observations in the past year have revealed unexpected similarities between the SCF and the APC and have allowed detailed insight into the regulation of their activities. Both complexes are now known to exist in different forms that target different substrates for ubiquitin-dependent proteolysis.

Anaphase-Promoting Complex-Cyclosome↗

PubMed1998

Localization of the gene for familial partial lipodystrophy (Dunnigan variety) to chromosome 1q21-22.

Obesity is strongly implicated in the pathophysiology of insulin resistance, diabetes mellitus and dyslipidemia. The mechanisms, however, by which obesity causes these complications are not known. The study of single-gene disorders affecting adipose tissue may elucidate some of the mechanisms involved in these processes. Familial partial lipodystrophy, Dunnigan variety, (FPLD, OMIM 308980) is an autosomal-dominant condition characterized by marked loss of subcutaneous adipose tissue affecting the trunk and extremities but with excess fat deposition in the head and neck areas. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus, dyslipidemia and acanthosis nigricans. The genetic basis of FPLD is unknown. We carried out a genome-wide scan with a set of highly polymorphic short tandem-repeats (STR) in individuals from five well-characterized pedigrees and mapped the FPLD locus to chromosome 1q21-22. The maximum two-point lod score obtained with a highly polymorphic microsatellite at D1S2624 at theta(max)=0 was 5.84. Multipoint-linkage analysis yielded a peak lod score of 8.25 between D1S305 and D1S1600. There was no evidence for genetic heterogeneity (alpha=1) in the pedigrees.

Chromosomes, Human, Pair 1↗

PubMed1998

Regulation of the cyclin B degradation system by an inhibitor of mitotic proteolysis.

The initiation of anaphase and exit from mitosis depend on the anaphase-promoting complex (APC), which mediates the ubiquitin-dependent proteolysis of anaphase-inhibiting proteins and mitotic cyclins. We have analyzed whether protein phosphatases are required for mitotic APC activation. In Xenopus egg extracts APC activation occurs normally in the presence of protein phosphatase 1 inhibitors, suggesting that the anaphase defects caused by protein phosphatase 1 mutation in several organisms are not due to a failure to activate the APC. Contrary to this, the initiation of mitotic cyclin B proteolysis is prevented by inhibitors of protein phosphatase 2A such as okadaic acid. Okadaic acid induces an activity that inhibits cyclin B ubiquitination. We refer to this activity as inhibitor of mitotic proteolysis because it also prevents the degradation of other APC substrates. A similar activity exists in extracts of Xenopus eggs that are arrested at the second meiotic metaphase by the cytostatic factor activity of the protein kinase mos. In Xenopus eggs, the initiation of anaphase II may therefore be prevented by an inhibitor of APC-dependent ubiquitination.

Anaphase↗