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PubMed1998

Iron-limited biofilms of Candida albicans and their susceptibility to amphotericin B.

Biofilms of Candida albicans were grown in vitro under iron limitation and at a low growth rate to simulate conditions for implant-associated biofilms in vivo. Their properties were compared with those of glucose-limited biofilms grown under analogous conditions. At steady state, the adherent cell populations of iron-limited biofilms were double those of glucose-limited biofilms, although the growth rates were similar (0.038 to 0.043 h-1). Both biofilm types were resistant to amphotericin B, but daughter cells from iron-limited biofilms were significantly more susceptible to the drug than those from glucose-limited biofilms.

Amphotericin B↗
PubMed1979

Macromolecular composition of a Cellulomonas sp. cultivated in continuous culture under glucose and zinc limitation.

The mutant strain of Cellulomonas sp. (ATCC 21399) was cultivated under glucose and zinc limitation at a variety of growth rates in continuous culture. The growth characteristics and macromolecular composition of the population varied with the limitation imposed and the growth rate. Glucose- and zinc-limited cultures maintained a constant relative protein content. The relative ribonucleic acid content increased, whereas the carbohydrate and deoxyribonucleic acid contents decreased with an increase in the population growth rate in glucose-limited cultures. Free unbound lipid remained constant. The maximum population growth rate in zinc-limited cultures was directly proportional to the zinc concentration and demonstrated a traditional steady-state function. The nucleic acid content increased with increased growth rate; however, the relative nucleic acid content was significantly depressed when compared to glucose limited cells. This manner of cultivation may prove to be a useful tool for the production of single cell protein with lowered nucleic acid content and the elucidation of micronutrient involvement in growth-related processes.

Actinomycetales↗
PubMed1992

Flocculence of Saccharomyces cerevisiae cells is induced by nutrient limitation, with cell surface hydrophobicity as a major determinant.

Initiation of flocculation ability of Saccharomyces cerevisiae MPY1 cells was observed at the moment the cells stop dividing because of nitrogen limitation. A shift in concentration of the limiting nutrient resulted in a corresponding shift in cell division and initiation of flocculence. Other limitations also led to initiation of flocculence, with magnesium limitation as the exception. Magnesium-limited S. cerevisiae cells did not flocculate at any stage of growth. Cell surface hydrophobicity was found to be strongly correlated with the ability of the yeast cells to flocculate. Hydrophobicity sharply increased at the end of the logarithmic growth phase, shortly before initiation of flocculation ability. Treatments of cells which resulted in a decrease in hydrophobicity also yielded a decrease in flocculation ability. Similarly, the presence of polycations increased both hydrophobicity and the ability to flocculate. Magnesium-limited cells were found to be strongly affected in cell surface hydrophobicity. A proteinaceous cell surface factor(s) was identified as a flocculin. This heat-stable component had a strong emulsifying activity, and appears to be involved in both cell surface hydrophobicity and in flocculation ability of the yeast cells.

Amino Acids↗
PubMed1993

Nitrogen limitation and nitrogen fixation during alkane biodegradation in a sandy soil.

We investigated nutrient limitations during hydrocarbon degradation in a sandy soil and found that fixed nitrogen was initially a limiting nutrient but that N limitation could sometimes be overcome by N2 fixation. Hydrocarbon biodegradation was examined in an unsaturated sandy soil incubated aerobically at 20 degrees C with propane or butane and various added nutrients. Propane and butane degradation proceeded similarly during the first 3 months of incubation. That is, bacteria in soil amended with N oxidized these hydrocarbons more rapidly than in controls without nutrient additions or in soil with added phosphate or trace minerals. Both propane- and butane-amended soil apparently became N limited after the initial available inorganic N was utilized, as indicated by a decrease in the rates of hydrocarbon degradation. After 3 months, propane and butane degradation proceeded differently. Bacteria in propane-degrading soil apparently remained N limited because propane degradation rates stayed low unless more N was added. In contrast, bacteria in butane-degrading soil appeared to overcome their N limitation because butane degradation rates later increased regardless of whether more N was added. Analyses of total N and acetylene reduction assays supported this apparent surplus of N in butane-amended soil. Total N was significantly (P < 0.01) higher in soil incubated with butane and no N amendments than in soil incubated with propane, even when the latter was amended with N. Acetylene reduction occurred only in butane-amended soil. These results indicate that N2 fixation occurred in butane-amended soil but not in propane-amended soil.

Acetylene↗
PubMed1997

Competition for cellulose among three predominant ruminal cellulolytic bacteria under substrate-excess and substrate-limited conditions.

Three predominant ruminal cellulolytic bacteria (Fibrobacter succinogenes S85, Ruminococcus flavefaciens FD-1, and Ruminococcus albus 7) were grown in different binary combinations to determine the outcome of competition in either cellulose-excess batch culture or in cellulose-limited continuous culture. Relative populations of each species were estimated by using signature membrane-associated fatty acids and/or 16S rRNA-targeted oligonucleotide probes. Both F. succinogenes and R. flavefaciens coexisted in cellulose-excess batch culture with similar population sizes (58 and 42%, respectively; standard error, 12%). By contrast, under cellulose limitation R. flavefaciens predominated (> 96% of total cell mass) in coculture with F. succinogenes, regardless of whether the two strains were inoculated simultaneously or whether R. flavefaciens was inoculated into an established culture of F. succinogenes. The predominance of R. flavefaciens over F. succinogenes under cellulose limitation is in accord with the former's more rapid adherence to cellulose and its higher affinity for cellodextrin products of cellulose hydrolysis. In batch cocultures of F. succinogenes and R. albus, the populations of the two species were similar. However, under cellulose limitation, F. succinogenes was the predominant strain (approximately 80% of cell mass) in cultures simultaneously coinoculated with R. albus. The results from batch cocultures of R. flavefaciens and R. albus were not consistent within or among trials: some experiments yielded monocultures of R. albus (suggesting production of an inhibitory agent by R. albus), while others contained substantial populations of both species. Under cellulose limitation, R. flavefaciens predominated over R. albus (85 and 15%, respectively), as would be expected by the former's greater adherence to cellulose. The retention of R. albus in the cellulose-limited coculture may result from a combination of its ability to utilize glucose (which is not utilizable by R. flavefaciens), its demonstrated ability to adapt under selective pressure in the chemostat to utilization of lower concentrations of cellobiose, a major product of cellulose hydrolysis, and its possible production of an inhibitory agent.

Animals↗
PubMed1997

Poly(3-Hydroxybutyrate) Production with High Productivity and High Polymer Content by a Fed-Batch Culture of Alcaligenes latus under Nitrogen Limitation.

Alcaligenes latus has been known to produce poly(3-hydroxybutyrate) (PHB) in a growth-associated manner even under nutrient-sufficient conditions. However, the PHB content obtained by fed-batch culture was always low, at ca. 50%, which makes the recovery process inefficient. In this study, the effect of applying nitrogen limitation on the production of PHB by A. latus was examined. In flask and batch cultures, the PHB synthesis rate could be increased considerably by applying nitrogen limitation. The PHB content could be increased to 87% by applying nitrogen limitation in batch culture, which was considerably higher than that typically obtainable (50%) under nitrogen-sufficient conditions. In fed-batch culture, cells were first cultured by the DO-stat feeding strategy without applying nitrogen limitation. Nitrogen limitation was applied at a cell concentration of 76 g (dry cell weight)/liter, and the sucrose concentration was maintained within 5 to 20 g/liter. After 8 h of nitrogen limitation, the cell concentration, PHB concentration, and PHB content reached 111.7 g (dry cell weight)/liter, 98.7 g/liter, and 88%, respectively, resulting in a productivity of 4.94 g of PHB/liter/h. The highest PHB productivity, 5.13 g/liter/h, was obtained after 16 h.

Journal Article↗
PubMed1985

Regulation of glycolytic rate in Streptococcus sanguis grown under glucose-limited and glucose-excess conditions in a chemostat.

The biochemical mechanisms of the acidogenic potential of Streptococcus sanguis ATCC 10556 grown in glucose-excess and glucose-limited continuous culture were studied. The rate of acid production during the glucose metabolism by the cells grown under glucose limitation (glucose-limited cells) was 2.1 to 2.6 times that by the cells grown in an excess of glucose (glucose-excess cells). When the glucose-limited cells were metabolizing glucose, intracellular concentrations of glucose 6-phosphate, fructose 6-phosphate, 3-phosphoglycerate, and pyruvate were higher, and that of glyceraldehyde 3-phosphate was lower, than those when the glucose-excess cells were metabolizing glucose. The levels of fructose 1,6-bisphosphate and dihydroxyacetone phosphate were not significantly different between these cells. The activities of glucose-phosphoenolpyruvate phosphotransferase system in decriptified cells and glyceraldehyde-3-phosphate dehydrogenase in cell-free extracts of the glucose-limited cells were higher than those in the glucose-excess cells. The activities of glucokinase, phosphoglycerate kinase, and pyruvate kinase in cell-free extracts of these cells were not different significantly. We conclude that the high glycolytic activity of the glucose-limited cells results from the increase in the synthesis of glucose-phosphoenolpyruvate phosphotransferase and glyceraldehyde-3-phosphate dehydrogenase.

Culture Media↗
PubMed1980

Reserve carbohydrate metabolism in Saccharomyces cerevisiae: responses to nutrient limitation.

The amounts of glycogen and trehalose have been measured in cells of a prototrophic diploid yeast strain subjected to a variety of nutrient limitations. Both glycogen and trehalose were accumulated in cells deprived specifically of nirogen, sulfur, or phosphorus, suggesting that reserve carbohydrate accumulation is a general response to nutrient limitation. The patterns of accumulation and utilization of glycogen and trehalose were not identical under these conditions, suggesting that the two carbohydrates may play distinct physiological roles. Glycogen and trehalose were also accumulated by cells undergoing carbon and energy limitation, both during diauxic growth in a relatively poor medium and during the approach to stationary phase in a rich medium. Growth in the rich medium was shown to be carbon or energy limited or both, although the interaction between carbon source limitation and oxygen limitation was complex. In both media, the pattern of glycogen accumulation and utilization was compatible with its serving as a source of energy both during respiratory adaptation and during a subsequent starvation. In contrast, the pattern of trehalose accumulation and utilization seemed compatible only with the latter role. In cultures that were depleting their supplies of exogenous glucose, the accumulation of glycogen began at glucose concentrations well above those sufficient to suppress glycogen accumulation in cultures growing with a constant concentration of exogenous glucose. The mechanism of this effect is not clear, but may involve a response to the rapid rate of change in the glucose concentration.

Culture Media↗
PubMed1993

Growth and metabolism of Saccharomyces cerevisiae in chemostat cultures under carbon-, nitrogen-, or carbon- and nitrogen-limiting conditions.

Aerobic chemostat cultures of Saccharomyces cerevisiae were performed under carbon-, nitrogen-, and dual carbon- and nitrogen-limiting conditions. The glucose concentration was kept constant, whereas the ammonium concentration was varied among different experiments and different dilution rates. It was found that both glucose and ammonium were consumed at the maximal possible rate, i.e., the feed rate, over a range of medium C/N ratios and dilution rates. To a small extent, this was due to a changing biomass composition, but much more important was the ability of uncoupling between anabolic biomass formation and catabolic energy substrate consumption. When ammonium started to limit the amount of biomass formed and hence the anabolic flow of glucose, this was totally or at least partly compensated for by an increased catabolic glucose consumption. The primary response when glucose was present in excess of the minimum requirements for biomass production was an increased rate of respiration. The calculated specific oxygen consumption rate, at D = 0.07 h-1, was more than doubled when an additional nitrogen limitation was imposed on the cells compared with that during single glucose limitation. However, the maximum respiratory capacity decreased with decreasing nitrogen concentration. The saturation level of the specific oxygen consumption rate decreased from 5.5 to 6.0 mmol/g/h under single glucose limitation to about 4.0 mmol/g/h at the lowest nitrogen concentration tested. The combined result of this was that the critical dilution rate, i.e., onset of fermentation, was as low as 0.10 h-1 during growth in a medium with a low nitrogen concentration compared with 0.20 h-1 obtained under single glucose limitation.

Ammonium Sulfate↗
PubMed1999

Physiological characterization of Pseudomonas aeruginosa during exotoxin A synthesis: glutamate, iron limitation, and aconitase activity.

Glutamate enhances the yield of exotoxin A (ETA), which is induced by iron limitation, from Pseudomonas aeruginosa. We tested the possibility that glutamate affects growth during iron restriction. We confirmed that iron limitation caused early entry into stationary phase but had no effect on the exponential growth rate. We showed that glutamate, as well as citrate and isocitrate, partially overcame this growth limitation. Glutamate had no effect on toxA (ETA-encoding) transcription, which implies that glutamate primarily increases the number of toxin-producing cells. In contrast, citrate and isocitrate diminished toxA transcription. Since glutamate, citrate, and isocitrate stimulated growth, we suspected a block in the citric acid cycle. Iron limitation reduced the activity of the iron-containing aconitase 12-fold but had no effect on isocitrate dehydrogenase activity, which was assayed as a control. There is a reciprocal relationship between aconitase activity and ETA synthesis, and this correlation does not appear to be coincidental because aconitase-specific effectors affect ETA synthesis. We tested whether a metabolic block is sufficient to induce ETA synthesis, but an aconitase-specific inhibitor diminished ETA production, which argues against this possibility. Finally, we present preliminary evidence that iron limitation may reversibly and posttranslationally inactivate aconitase in vivo. In summary, the environmental factors that stimulate ETA synthesis are related: glutamate bypasses an iron limitation-dependent metabolic block that causes entry into stationary phase. We speculate that one or more of the aconitases in P. aeruginosa may contribute to the control of virulence factor synthesis.

ADP Ribose Transferases↗
PubMed2002

Regulation of mutY and nature of mutator mutations in Escherichia coli populations under nutrient limitation.

Previous analysis of aerobic, glucose-limited continuous cultures of Escherichia coli revealed that G:C-to-T:A (G:C-->T:A) transversions were the most commonly occurring type of spontaneous mutation. One possible explanation for the preponderance of these mutations was that nutrient limitation repressed MutY-dependent DNA repair, resulting in increased proportions of G:C-->T:A transversions. The regulation of the mutY-dependent DNA repair system was therefore studied with a transcriptional mutY-lacZ fusion recombined into the chromosome. Expression from the mutY promoter was fourfold higher under aerobic conditions than under anaerobic conditions. But mutY expression was higher in glucose- or ammonia-limited chemostats than in nutrient-excess batch culture, so mutY was not downregulated by nutrient limitation. An alternative explanation for the frequency of G:C-->T:A transversions was the common appearance of mutY mutator mutations in the chemostat populations. Of 11 chemostat populations screened in detail, six contained mutators, and the mutator mutation in four cultures was located in the region of mutY at 66 min on the chromosome. The spectrum of mutations and rate of mutation in these isolates were fully consistent with a mutY-deficiency in each strain. Based on PCR analysis of the region within and around mutY, isolates from three individual populations contained deletions extending at least 2 kb upstream of mutY and more than 5 kb downstream. In the fourth population, the deletion was even longer, extending at least 5 kb upstream and 5 kb downstream of mutY. The isolation of mutY mutator strains from four independent populations with extensive chromosomal rearrangements suggests that mutY inactivation by deletion is a means of increasing mutation rates under nutrient limitation and explains the observed frequency of G:C-->T:A mutations in glucose-limited chemostats.

DNA Glycosylases↗
PubMed1965

EFFECTS OF GROWTH RATE AND LIMITING SUBSTRATE ON GLUCOSE METABOLISM IN ESCHERICHIA COLI.

Wright, D. N. (Iowa State University, Ames), and W. R. Lockhart. Effects of growth rate and limiting substrate on glucose metabolism in Escherichia coli. J. Bacteriol. 89:1082-1085. 1965.-Escherichia coli was grown in continuous culture at various rates in a defined medium with either glucose of (NH(4))(2)SO(4) as the rate-limiting substrate. Cellular content of polysaccharide ("glycogen") is greater in cells grown under nitrogen limitation with glucose available in excess, and is greater in rapidly grown than in slowly grown cells. The ability of cells to carry on endogenous respiration, as measured by tetrazolium reduction, can be correlated with their glycogen content. In carbon-limited cultures, the proportion of substrate glucose diverted to glycogen production is least for cells grown slowly, which may reflect greater energy requirements for cell maintenance in such cultures. The activity of glucose-6-phosphate dehydrogenase (indicating function of a C-1 preferential pathway for glucose degradation) is greater in rapidly grown cells, confirming earlier observations in batch cultures. Activity of this enzyme is also greater in nitrogen-limited than in carbon-limited cells, suggesting that there may be catabolic repression of the Embden-Meyerhoff pathway when glucose is available in excess.

Carbohydrate Metabolism↗
PubMed1995

Limiting long-term illness and its associations with mortality and indicators of social deprivation.

STUDY OBJECTIVE: To examine geographical variation in limiting long-term illness in England and Wales and assesses the extent of its similarity with the distribution of mortality rates and of deprivation. DESIGN: A geographically based study using data from the 1991 census on limiting long term illness. Maps and regression analysis are used to compare the distribution of standardised illness ratios with standardised mortality ratios and indicators of social deprivation. SETTING: A total of 401 local authority districts in England and Wales. PARTICIPANTS: The population of England and Wales enumerated in the 1991 census. MAIN RESULTS: The geographical pattern of limiting long term illness shows many similarities with that of mortality but there are also some differences. Both are positively associated with indicators of social deprivation, with limiting long term illness tending to show stronger correlations, particularly in the elderly. Most of Wales and many industrial areas of northern England have higher rates of long term illness than would be expected from their mortality rates, while much of south eastern England has lower than expected rates. CONCLUSIONS: Moves towards using data on limiting long term illness instead of standardised mortality rates would have important implications for NHS resource allocations. Further assessment of the reliability of these data on self reported morbidity is required. in particular, there is a need to assess how much they reflect real differences in ill health rather than the influence of socioeconomic or cultural factors affecting the likelihood of a positive answer to the census question on limiting long term illness.

Adolescent↗
PubMed1997

Effect of labour market conditions on reporting of limiting long-term illness and permanent sickness in England and Wales.

STUDY OBJECTIVE: To identify any bias in the reporting of limiting long term illness and permanent sickness due to labour market conditions, and show the absence of the effect in mortality rates. DESIGN: A geographically based study using data from the 1991 census. Standardised ratios for mortality and long term illness in people aged 0-64 years and permanent sickness in people of working age were compared with Carstairs deprivation scores in multilevel models which separated the effects operating at three geographical scales: census wards, travel to work areas, and standard regions. Holding ward and regional effects constant, variations between travel to work areas were compared with long term unemployment rates. SETTING: Altogether 8690 wards and 262 travel to work areas in England and Wales. MAIN RESULTS: Variations in mortality, limiting long term illness, and permanent sickness were related to Carstairs deprivation scores and standard region. With these relationships controlled, limiting long term illness and permanent sickness were significantly related to long term unemployment levels in travel to work areas, but mortality was not affected. Self reported morbidity was more sensitive to variations in long term unemployment rates in conditions of high social deprivation than in affluent populations. CONCLUSIONS: Limiting long term illness and permanent sickness measures may reflect a tendency for higher positive response in difficult labour market conditions. For average social deprivation conditions, standardised limiting long term illness for people aged 0-64 years was 20% higher in travel to work areas where employment prospects were relatively poor compared with areas with relatively good employment prospects. This casts doubt on the use of limiting long term illness as an indicator of objective health care needs for resource allocation purposes at national level.

Adolescent↗
PubMed2001

Occupational exposure limits for chemicals.

Occupational exposure limits (OELs) are tools to help employers protect the health of those who may be exposed to chemicals in their workplace. Under the United Kingdom Control of Substances Hazardous to Health (COSHH) Regulations they define adequate control by inhalation. OELs are set by the Health and Safety Commission (HSC) on advice from its Advisory Committee on Toxic Substances (ACTS) and after public consultation. Thus they are consensus limits which have the support of both sides of industry. COSHH uses two types of occupational exposure limit-the occupational exposure standard (OES) and the maximum exposure limit (MEL). OESs are set for substances for which it is possible to identify a concentration at which there is no significant risk to health. Employers are required to meet the limit, there is no requirement to go below it, and it can be exceeded provided steps are taken to meet it as soon as reasonably practicable. MELs are set for substances which have serious health implications and for which an OES cannot be set. Most of the substances with MELs are either carcinogens or causes of occupational asthma. Employers must not exceed an MEL and must reduce exposure as far below it as is reasonably practicable. MELs are set at concentrations achievable by good occupational hygiene practice such that risks to workers are judged to be reduced to a tolerable level. The HSC consider that this approach is preferable to the use of mathematical models to generate risk estimates, which inevitably gives a spurious appearance of accuracy. The MEL/OES system is poorly understand by many employers who use chemicals, is not comprehensive as some substances meet neither the OES nor MEL criteria, and does not mesh well with indicative occupational exposure limit values which will increasingly be set under the European Union Chemical Agents Directive. COSHH essentials: easy steps to control chemicals provides the practical help that firms need to control chemicals. It takes users straight from hazard and exposure considerations to benchmark standards of good practice. The problems with the current system have prompted ACTS to set up a subgroup to review the OEL framework.

Chemical Industry↗
PubMed1978

Energy transduction in the mitochondrionlike bacterium Paracoccus denitrificans during carbon- or sulphate-limited aerobic growth in continuous culture.

Paracoccus denitrificans was grown in carbon-limited aerobic continuous culture (critical dilution rate (Dc) = 0.48 h-1). The molar growth yield for carbon (succinate or malate) was constant at about 60 over a broad dilution range (growth rate) from 0.10 to 0.48 h-1. Measurements of the stoichiometry of proton translocation associated with the oxidation of endogenous substrates yielded a ratio of protons ejected from the cell per atom of oxygen consumed(leads to H+:O) of 8.55 which decreased to 5.85 in the presence of piericidin A (PA), a specific inhibitor of NADH dehydrogenase (EC 1.6.99.3). With starved cells, the observed leads to H+:O associated with the oxidation of added succinate in the presence of PA was 5.61. These observed leads to H:O's represent an underestimation since no correction was made for proton backflow during the short interval of respiratory activity. Aerobic growth of Pc. denitrificans in the chemostat becomes sulphate limited at entering concentrations of sulphate less than 300 is microM. Neither the maximum specific growth rate (measured at Dc) nor the observed molar growth yield for succinate decreased under sulphate limitation. The NADH oxidase in electron transport particles prepared from sulphate-limited cells was completely inhibited by PA. The stoichiometry of proton translocation associated with malate oxidation was similarly unaffected by sulphate limitation. It is concluded that (a) the respiratory chain of aerobic, heterotrophically grown Pc. denitrificans possesses three sites of energy conservation, including site III, (b) the number of protons ejected during the transfer of one pair of reducing equivalents along a region of the electron transport chain equivalent to a single energy-coupling site is 3, and (c) that sulphate limitation does not lead to a loss of proton translocation associated with the cytochrome-independent region of the respiratory chain.

Aerobiosis↗
PubMed2003

Distinguishing features of self-limiting adult small-bowel intussusception identified at CT.

PURPOSE: To determine if clinical or computed tomographic (CT) findings can be used to distinguish self-limiting cases of adult small-bowel intussusception from those requiring surgery. MATERIALS AND METHODS: Thirty-seven cases of adult small-bowel intussusception were identified by a retrospective computerized search of 69,040 abdominopelvic CT examinations performed over a 4-year period. Two independent readers recorded CT features. Clinical findings and outcomes were determined by review of all available medical records. Outcome was classified as either surgical or self-limiting. Association between predictive variables and outcome was assessed by the Fisher exact test and logistic regression models. A multivariate, stepwise, logistic regression model was used to determine the best predictors of outcome. RESULTS: Six patients (16%) underwent surgery, and all had lead-point tumors. Thirty-one patients were cared for conservatively (84%) and none required surgery at a mean follow-up of 5.2 months (range, 0-46 months). Multivariate, stepwise, logistic regression analysis showed intussusception length was the only variable that was independently predictive of outcome. All 20 patients with an intussusception length of 3.5 cm or less, as measured by either reader, had cases that were self-limiting. Seventeen patients had an intussusception length greater than 3.5 cm, as measured by either reader. Eleven patients had an intussusception that was self-limiting, and six patients had an intussusception that required surgery. CONCLUSION: Intussusception length is the main factor in distinguishing the majority of small-bowel intussusceptions detected at CT that are self-limiting from the minority that require surgery. An intussusception that is shorter than 3.5 cm is likely to be self-limiting.

Adult↗
PubMed2006

Suppressor of cytokine signaling-2 limits intestinal growth and enterotrophic actions of IGF-I in vivo.

Suppressors of cytokine signaling (SOCS) typically limit cytokine receptor signaling via the JAK-STAT pathway. Considerable evidence demonstrates that SOCS2 limits growth hormone (GH) action on body and organ growth. Biochemical evidence that SOCS2 binds to the IGF-I receptor (IGF-IR) supports the novel possibility that SOCS2 limits IGF-I action. The current study tested the hypothesis that SOCS2 normally limits basal or IGF-I-induced intestinal growth and limits IGF-IR signaling in intestinal epithelial cells. Intestinal growth was assessed in mice homozygous for SOCS2 gene deletion (SOCS2 null) and wild-type (WT) littermates at different ages and in response to infused IGF-I or vehicle or EGF and vehicle. The effects of SOCS2 on IGF-IR signaling were examined in ex vivo cultures of SOCS2 null and WT intestine and Caco-2 cells. Compared with WT, SOCS2 null mice showed significantly enhanced small intestine and colon growth, mucosal mass, and crypt cell proliferation and decreases in radiation-induced crypt apoptosis in jejunum. SOCS2 null mice showed significantly greater growth responses to IGF-I in small intestine and colon. IGF-I-stimulated activation of IGF-IR and downstream signaling intermediates were enhanced in the intestine of SOCS2 null mice and were decreased by SOCS2 overexpression in Caco-2 cells. SOCS2 bound directly to the endogenous IGF-IR in Caco-2 cells. The intestine of SOCS2 null mice also showed enhanced growth responses to infused EGF. We conclude that SOCS2 normally limits basal and IGF-I- and EGF-induced intestinal growth in vivo and has novel inhibitory effects on the IGF-IR tyrosine kinase pathway in intestinal epithelial cells.

Aging↗