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1.
Homo ; 74(1): 33-44, 2023 Apr 14.
Article in English | MEDLINE | ID: mdl-36752673

ABSTRACT

With the implementation of the three-child policy in China, the debate between fertility and health and longevity has again become a hot topic in the era of increasing ageing. This study aimed to explore the association between reproductive behaviour and longevity of older women and men in China. Based on data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) from 2014 to 2018, a total of 1428 deceased older people were enrolled in the study, including 421 centenarians and 1007 non-centenarians. The analysis of the association between fertility and longevity was conducted in the multivariate logistic regression. Compared to women aged 99 years and below, centenarian women had significantly fewer children (p < 0.01), fewer sons (p < 0.01) and fewer daughters. Centenarian men had more children, more daughters and fewer sons. For both men and women, centenarians were significantly characterized by later age at first birth (p < 0.01) and later age at last birth (p < 0.01). Centenarians were significantly characterized by having children and having a daughter, however, non-centenarians were significantly characterized by having a son (p < 0.01). The association between fertility and health of both men and women should be taken into account in the development of fertility policies and supporting policies. Fertility levels should be increased without compromising the health benefits of individuals in their later years.


Subject(s)
Fertility , Longevity , Reproductive Behavior , Aged , Female , Humans , Male , Aging , East Asian People/statistics & numerical data , Reproductive Behavior/statistics & numerical data , China/epidemiology , Aged, 80 and over
2.
BMC Geriatr ; 22(1): 701, 2022 08 24.
Article in English | MEDLINE | ID: mdl-35999498

ABSTRACT

PURPOSE: This study aimed to evaluate the role of social participation in the relationship between internet use and depressive symptoms among Chinese older adults and investigate how the internet use interact with social participation to reduce the risk of depressive symptoms. METHODS: Based on the survey from the China Health and Retirement Longitudinal Study (CHARLS) in 2018, we identified 4645 subjects and used the Ordinary Least Square method (OLS) and Propensity Score Matching method (PSM) to identify the association between Internet use and depression of older people, and further test how social participation played a role in the relationship. RESULTS: The level of depression of older people was significantly reduced in those who using internet in China, and the effect was still robust under different identification methods. The mental health was improved when using internet because of the increase of social participation and social capital. Further, The positive effect was stronger especially in those who were female, living in rural areas, has low education attainments and were 70-79 years old. CONCLUSIONS: The popularity of internet use has a positive effect on the depressive symptoms of Chinese older adults. Effective measures were encouraged to improve the friendliness of internet for older people and promote the popularization of the Internet and older group, achieving the spiritual well-being of them in the Internet society.


Subject(s)
Internet Use , Social Participation , Aged , China/epidemiology , Female , Humans , Longitudinal Studies , Male , Retirement/psychology , Social Participation/psychology
3.
Am J Hum Biol ; 34(10): e23786, 2022 10.
Article in English | MEDLINE | ID: mdl-35929732

ABSTRACT

OBJECTIVES: The relationship between fertility history and human health has long fascinated scholars; however, whether there is a link between number of children and cognitive function in older adults remains unclear. We investigated the associations between parity and the timing of first and last births with the cognitive function of older adults over 65. METHODS: The mini-mental state examination (MMSE) was selected as a tool to measure cognitive function. We analyzed data on 5847 older adults in rural and urban communities in China from the 2018 Chinese Longitudinal Healthy Longevity Survey using ordinary least squares. To further explore the transmission mechanism, we also conducted a mediating effect analysis. RESULTS: We found a negative association between number of children and cognitive function in older adults. Compared with older adults with four children, the MMSE scores of older adults with more than five children decreased significantly, and the score of older adults with zero to three children increased. Further, a late age at first birth (≥35) and a late age at last birth (≥35) were negatively associated with cognitive function. We also found that the associations between parity and cognition might be partly explained by variations in health. CONCLUSION: Our analyses provided evidence from China to support the link between fertility history and cognitive function that has been observed in previous international studies: We suggest that high parity (≥5) is negatively associated with cognitive function.


Subject(s)
Cognitive Dysfunction , Aged , Child , China/epidemiology , Cognition , Cognitive Dysfunction/psychology , Female , Fertility , Humans , Rural Population
4.
Front Med (Lausanne) ; 9: 798787, 2022.
Article in English | MEDLINE | ID: mdl-35559347

ABSTRACT

As an important life event in individuals' life, childbirth will affect the health of women to different degrees. More and more attention has been paid to whether the number of births will affect the incident diabetes in elderly women, but there are few related studies. Based on the data of the Chinese Longitudinal Healthy Longevity Survey in 2018, 6,159 older women are selected as the study population. Logistic regression analyses are used to estimate the relationship between the number of births and diabetes risk. For each additional birth, the odds ratio of maternal diabetes will decrease by 6.9% and the result is significant at the 1% level, especially among mothers having four children or less. The conclusion is equally applicable in the sample of fathers and urban mothers, but the increase in the number of births will increase the risk of diabetes in rural mothers, although this result is not statistically significant. Later age at first birth, later age at last birth, the longer childbearing period, and birth interval will significantly reduce the risk of diabetes.

5.
BMC Public Health ; 22(1): 682, 2022 04 07.
Article in English | MEDLINE | ID: mdl-35392851

ABSTRACT

BACKGROUND: This study evaluates the impact of fertility during the childbearing period on the longevity of older rural Chinese women and verifies whether any trade-off exists between women's longevity and their number of children to provide empirical evidence for improving health intervention policies and formulating active fertility policies in low-fertility countries. METHODS: Based on the data of the deaths of 1623 older adults aged 65 and above during 2014-2018 in the Chinese Longitudinal Healthy Longevity Survey, this study explores the relationship between the number of children born and older rural women's longevity using the ordinary least squares method. Furthermore, the impact of fertility on the longevity of men and women in rural and urban areas, along with other reproductive behaviours on older rural women's longevity, were analysed. RESULTS: There was a significant negative correlation between the number of children born and women's longevity (ß = - 0.555, p < 0.05). Additionally, their longevity exhibited a decreasing trend with having birthed more sons and an increasing trend with more daughters. Age at first and last births had a significant positive relationship with rural women's longevity; however, the effect of fertility on the longevity of older rural and urban men and older urban women was not significant. CONCLUSIONS: It is confirmed that there is a trade-off between fertility and longevity for rural women in China. Future research should focus on compensating for the decline in female longevity caused by the number of children born and promote the concept of a healthy pregnancy, scientific nurture, and gender equality in fertility.


Subject(s)
Fertility , Rural Population , Aged , Child , China , Developing Countries , Female , Humans , Longevity , Longitudinal Studies , Male , Population Dynamics , Pregnancy , Socioeconomic Factors , Urban Population
6.
Front Public Health ; 10: 777178, 2022.
Article in English | MEDLINE | ID: mdl-35284360

ABSTRACT

Purpose: The social support theory suggested that involving older people in social activities could increase their level of social participation and interaction, which in turn improved their well-being. However, there has been a heated controversy about whether participating in volunteer services could enhance the well-being of older people, especially for the Chinese sample. Method: Based on the data from the China Health and Retirement Longitudinal Study (CHARLS) in 2013, this paper used an ordered probit model to examine the impact of older people's participation in volunteer services on their well-being, as well as the differences in the impact across groups and the specific transmission mechanism. Result: The empirical study found that Chinese older people's participation in volunteerism significantly enhanced their well-being, which remained robust after eliminating the possible effects of self-selection. Further heterogeneity analysis revealed that for female, non-party members and older adults with good economic status, participation in volunteerism has a higher increase in well-being. The mediating effect test indicated that older people's participation in volunteerism affected well-being mainly through enhancing positive emotions. Conclusion: It is necessary to promote the participation of older people in volunteer services and to clarify the role of government support and advocacy. Proper guidance is given to change the role of older people as care recipients to that of service providers and caregivers, and to continuously enrich the programmes and content of volunteer service to safeguard the well-being of older people.


Subject(s)
Social Participation , Volunteers , Aged , China , Female , Humans , Longitudinal Studies , Social Support
7.
Front Psychiatry ; 12: 739085, 2021.
Article in English | MEDLINE | ID: mdl-34950065

ABSTRACT

This study investigated the effect of using the Internet on depression symptoms of older Chinese, based on 7,801 adults aged over 60 years from the 2018 China Family Panel Studies. Results showed that the elderly who used the Internet reported lower depression scores, and the more frequent they use Internet, the lower their depression scores. Moreover, using the Internet for social contact and entertainment decreased the depression scores of the older adults, but when using Internet for learn, work, and commercial activity, the relief of depressive symptoms disappeared. Therelief of depression symptoms through Internet use were heterogeneous among different groups: the elderly aged 60-70, women, rural residents, and those with lower education attainment. Moreover, Internet use decreased the depression scores by increasing the frequency of contact with their children and increasing the importance of their enjoyment of life. According to the relief of depression by using Internet reasonably, policies should be designed to ensure that all ages could have easy access to the Internet.

8.
Front Sociol ; 6: 675968, 2021.
Article in English | MEDLINE | ID: mdl-34950729

ABSTRACT

There is little literature on the impact of donation on individual wellbeing in China. This study examines individual donations in China to answer the question of whether helping others makes us happier and to provide policy implications for in Chinese context. Based on the 2012 Chinese General Social Survey (CGSS) data and using ordered logit and OLS as benchmark models, this study finds that donation can significantly increase individual happiness. After using propensity score matching (PSM) to eliminate the possible impact of self-selection, the above conclusion remains robust. After a sub-sample discussion, it is found that this effect is more pronounced under completely voluntary donation behavior, and is not affected by economic factors, indicating that the happiness effect of donation does not vary significantly depending on the individual's economic status. This study contributes to the literature on donation behavior by examining the impact of donation behavior on donors' subjective happiness in China, and further identifies subjective happiness differences, as between voluntary and involuntary donations, thereby providing theoretical and empirical support for the formulation of policies for the development of donation institutions in China.

9.
Front Psychiatry ; 12: 731378, 2021.
Article in English | MEDLINE | ID: mdl-34650455

ABSTRACT

There is little empirical research on the effect of working after retirement on the mental health of the older adults in China. To fill this gap in the literature, this study examines the effects of working after retirement on the mental health of the older adults using data from the China Family Panel Studies. We employed the methods of ordinary least squares, ordered logit, and propensity score matching-difference in differences (PSM-DID). Results show that working after retirement is negatively related to mental health of the older adults in China. The deterioration effect of post-retirement work mainly impacts those aged over 60 years, women, and those with lower education background, urban household registration, higher pension, and higher social status. Working after retirement is negatively related to mental health through the mediating effects of deteriorating interpersonal relationships and lower positive attitude. It is necessary to consider mental health effects and their population differences to evaluate the impact and improve the quality of policies of active aging.

10.
Front Public Health ; 9: 673368, 2021.
Article in English | MEDLINE | ID: mdl-34336769

ABSTRACT

Purpose: The Internet has become an important part of daily life. However, older adults in China remain digital refugees amid the rapid development of digital information technology. This study attempts to scientifically answer how Internet use affects the subjective welfare of older adults. Method: Using data from the 2014 and 2016 China Longitudinal Aging Social Survey (CLASS), a combination of ordinary least squares, ordered logit regression models, and propensity score matching (PSM) models were used to analyze the effects of Internet use on the mental health of Chinese older adults. Results: Our findings suggest that Internet use affects the mental health of older adults and increases the incidence of their depressive symptoms. These findings are robust to changing the key indicators, research method, and sample. Further heterogeneity analysis reveals that the negative effects on mental health are more evident for specific groups of older adults, such as those who are women, younger and middle-aged, high-income, non-rural Hukou, less educated, and living with others. Conclusions: Cultivating the ability of older adults to use the Internet and maintain a rational attitude while doing so can prevent its negative impact on their life satisfaction. Moreover, it can improve their attitudes toward using the technology and reduce their anxiety.


Subject(s)
Internet Use , Mental Health , Aged , Aging , Attitude , China/epidemiology , Female , Humans , Middle Aged
11.
Front Public Health ; 9: 677643, 2021.
Article in English | MEDLINE | ID: mdl-34268289

ABSTRACT

Purpose: The research objectives of this study are to test the scientific propositions of whether Internet use promotes life satisfaction among the elderly, whether there is variability in the effect of Internet use on the well-being of the elderly, and through what channels Internet use affects the elderly's life satisfaction. Method: Using data from the 2017 Chinese General Social Survey (CGSS), this paper employed linear regression, ordered logit model, and the propensity score matching (PSM) approach to investigate the association of Internet use with life satisfaction among the elderly in China. Results: The results show that Internet use was significantly and negatively associated with the life satisfaction of the Chinese elderly. Further analysis on group heterogeneity demonstrates that the negative association was more prominent among the participants who were males, at a lower age, had lower income and education, non-agricultural registered, and relatively healthy. Finally, the mediating effect indicates that Internet use may affect life satisfaction among the elderly through the channel of reducing their perceptions of social justice. Conclusions: In order to avoid the negative effects of using the Internet, the following policy suggestions are put forward: Improve the elderly's attitudes toward Internet use; pay attention to the sense of fairness of the elderly to improve life satisfaction; guide the elderly to reduce the time of using the Internet.


Subject(s)
Internet Use , Personal Satisfaction , Aged , Attitude , China/epidemiology , Humans , Income , Male
12.
Sci Rep ; 7(1): 14579, 2017 11 06.
Article in English | MEDLINE | ID: mdl-29109532

ABSTRACT

NF-κB is a major regulator of gene transcription involved in immune, inflammation, apoptosis and stress responses. However, the regulation of NF-κB is not completely understood. Here, we report that the N-Myc and STATs Interactor (NMI), an IFN-inducible protein, is an important negative regulator of NF-κB activity. We found that NMI negatively regulates TNF-α-induced IL-6 and IL-1ß production in HeLa cells. Overexpression of NMI inhibits NF-κB transcriptional activity, in contrast, depletion of NMI by shRNA increases NF-κB transcriptional activity. Mechanistically, NMI associates with NF-κB/p65 and inhibits NF-κB/p65 nuclear translocation and thereby negatively regulates NF-κB/p65 transcriptional activity. Taken together, our results demonstrate that NMI modulates the NF-κB signaling pathway by sequestering NF-κB/p65 in the cytoplasm, resulting in reduced IL-6 and IL-1ß production after TNF-α stimulation. Treatment with IFNα in the presence of NMI leads to increased apoptosis in tumor cells. These findings reveal a novel mechanism by which NMI regulates NF-κB activity.


Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , NF-kappa B/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Transcription Factor RelA/metabolism , Transcription, Genetic , Tumor Necrosis Factor-alpha/metabolism , Cytoplasm/metabolism , HeLa Cells , Humans , Interleukin-6/metabolism , Signal Transduction
13.
Cancer Lett ; 376(1): 22-33, 2016 06 28.
Article in English | MEDLINE | ID: mdl-27012186

ABSTRACT

The epithelial-mesenchymal transition (EMT) plays an essential role in embryonic development, wound healing, tissue regeneration, organ fibrosis, and tumor progression. However, the mechanisms underlying this process are poorly understood. Many signaling pathways, including the NF-κB signaling pathway, trigger EMT during development and differentiation. In the present study, we report that N-Myc interactor (NMI) inhibits EMT progression by suppressing transcriptional activities of NF-κB in human gastric cancer cells. We show that the expression of NMI is significantly reduced in invasive gastric cancer cells and gastric cancer tissues. Overexpression of NMI inhibited cell migration and invasion, and this inhibition was enhanced after TNF-α stimulation. Tumorigenicity assay in nude mice support the notion that NMI inhibits EMT in cancer cells. Mechanistically, NMI promotes the interaction between NF-κB/p65 and histone deacetylases (HDACs) and inhibits the acetylation and transcriptional activity of p65. The expression of p65 rescues NMI-mediated inhibition of EMT and the inhibition of the acetylation of p65 mediated by NMI is HDACs-dependent. Taken together, these findings suggest that NMI can suppress tumor invasion and metastasis by inhibiting NF-κB pathways, providing an alternative mechanism for EMT inhibition in stomach neoplasm.


Subject(s)
Epithelial-Mesenchymal Transition , Intracellular Signaling Peptides and Proteins/metabolism , Stomach Neoplasms/metabolism , Transcription Factor RelA/metabolism , Acetylation , Animals , Cell Line, Tumor , Cell Movement , Epithelial-Mesenchymal Transition/drug effects , Gene Expression Regulation, Neoplastic , HEK293 Cells , Heterografts , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Humans , Intracellular Signaling Peptides and Proteins/genetics , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/secondary , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Male , Mice, Nude , Neoplasm Invasiveness , Neoplasm Transplantation , RNA Interference , Signal Transduction , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Time Factors , Transcription Factor RelA/genetics , Transcription, Genetic , Transfection , Tumor Necrosis Factor-alpha/pharmacology
14.
Mol Biol Cell ; 23(23): 4635-46, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23034180

ABSTRACT

The ARF tumor suppressor is a product of the INK4a/ARF locus, which is frequently mutated in human cancer. The expression of ARF is up-regulated in response to certain types of DNA damage, oncogene activation, and interferon stimuli. Through interaction with the p53 negative regulator MDM2, ARF controls a well-described p53/MDM2-dependent checkpoint. However, the mechanism of ARF induction is poorly understood. Using a yeast two-hybrid screen, we identify a novel ARF-interacting protein, N-Myc and STATs interactor (NMI). Previously, NMI was known to be a c-Myc-interacting protein. Here we demonstrate that through competitive binding to the ARF ubiquitin E3 ligase (ubiquitin ligase for ARF [ULF]), NMI protects ARF from ULF-mediated ubiquitin degradation. In response to cellular stresses, NMI is induced, and a fraction of NMI is translocated to the nucleus to stabilize ARF. Thus our work reveals a novel NMI-mediated, transcription-independent ARF induction pathway in response to cellular stresses.


Subject(s)
Intracellular Signaling Peptides and Proteins , Stress, Physiological/genetics , Transcriptional Activation/genetics , Tumor Suppressor Protein p14ARF , DNA Damage , Gene Expression Regulation, Neoplastic , HEK293 Cells , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Protein Binding , Proteolysis , Proto-Oncogene Proteins c-mdm2/genetics , Proto-Oncogene Proteins c-mdm2/metabolism , Tumor Suppressor Protein p14ARF/genetics , Tumor Suppressor Protein p14ARF/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Ubiquitin/genetics , Ubiquitin/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism
15.
Zhonghua Nei Ke Za Zhi ; 48(11): 940-3, 2009 Nov.
Article in Chinese | MEDLINE | ID: mdl-20079327

ABSTRACT

OBJECTIVE: To investigate insulin resistance and islet beta cell function in type 2 diabetes mellitus (T2DM) and non alcoholic fatty liver disease (NAFLD). METHODS: Two hundred and six study subjects were classified into 4 groups. Hepatic insulin resistance index (HIR), HOMA insulin resistance index (HOMA-IR) and Matsuda index (MSI) were used to assess insulin resistance. HOMA-beta, early and late phase indexes of insulin secretion were used to evaluate islet beta cell function. RESULTS: HIR in the NAFLD group and T2DM with NAFLD group were significantly higher than that in the control group and T2DM group (4.13 +/- 0.64, 4.03 +/- 0.69 vs 3.52 +/- 0.78, 3.53 +/- 0.64, P < 0.05), HOMA-IR in the T2DM with NAFLD group was significantly higher than that in the NAFLD group and T2DM group (3.35 +/- 2.69 vs 2.31 +/- 1.39, 2.40 +/- 1.55, P < 0.05). Early phase insulin secretion index in the NAFLD group was lower than that in the control group significantly (2.13 +/- 0.17 vs 2.61 +/- 0.13, P < 0.05), but there was no significant difference of HOMA-beta and late phase insulin secretion index between the NAFLD group and control group, HOMA-beta, early and late phase indexes of insulin secretion in the T2DM group and T2DM with NAFLD group were significantly lower than those in the control group. CONCLUSIONS: Normal glucose tolerance NAFLD patients may present with insulin resistance, mainly hepatic insulin resistance. Islet beta cell function in the NAFLD patients show damage of early phase insulin secretion. Newly diagnosed T2DM with or without NAFLD patients generally present with insulin resistance, early and later phase insulin secretion dysfunction. Insulin resistance in patients with T2DM and NAFLD is more severe.


Subject(s)
Diabetes Mellitus, Type 2 , Insulin Resistance , Diabetes Mellitus, Type 2/metabolism , Humans , Insulin/metabolism , Insulin Secretion , Insulin-Secreting Cells/metabolism , Non-alcoholic Fatty Liver Disease/metabolism
16.
Article in Chinese | MEDLINE | ID: mdl-17094622

ABSTRACT

OBJECTIVE: To evaluate the molluscicidal effect of the META-Li (40% META liquid formulation) against Oncomelania snails in laboratory and field. METHODS: The experiment of META-Li against the snails by spraying, immersion and climbing-inhibition test was carried out in laboratory. Spray method was performed in the field to compare with the wettable powder of 50% niclosamide ethanolamine salt. RESULTS: In laboratory, the LC50 of META-Li by spraying for 1, 2, 3 days was 0.78, 0.44 and 0.46 g/m2 respectively; by immersion method for 1, 2, 3 days, it was 44.4, 27.4 and 24.8 mg/L respectively. When sprayed with active ingredient 2 g/mW of META-Li in the field, the snail death rate was above 90% after 7 days, similar to that of niclosamide. CONCLUSION: META-Li shows high molluscicidal and climbing-inhibition effect on Oncomelania snails.


Subject(s)
Molluscacides/pharmacology , Snails/drug effects , Animals
17.
Mol Cell ; 13(3): 341-55, 2004 Feb 13.
Article in English | MEDLINE | ID: mdl-14967142

ABSTRACT

The protein-tyrosine phosphatase Shp2 plays an essential role in growth factor and integrin signaling, and Shp2 mutations cause developmental defects and/or malignancy. Previous work has placed Shp2 upstream of Ras. However, the mechanism of Shp2 action and its substrate(s) are poorly defined. Additional Shp2 functions downstream of, or parallel to, Ras/Erk activation also are proposed. Here, we show that Shp2 promotes Src family kinase (SFK) activation by regulating the phosphorylation of the Csk regulator PAG/Cbp, thereby controlling Csk access to SFKs. In Shp2-deficient cells, SFK inhibitory C-terminal tyrosines are hyperphosphorylated, and the tyrosyl phosphorylation of multiple SFK substrates, including Plcgamma1, is decreased. Decreased Plcgamma1 phosphorylation leads to defective Ras activation on endomembranes, and may help account for impaired Erk activation in Shp2-deficient cells. Decreased phosphorylation/activation of other SFK substrates may explain additional consequences of Shp2 deficiency, including altered cell spreading, stress fibers, focal adhesions, and motility.


Subject(s)
Mitogen-Activated Protein Kinases/metabolism , Protein Tyrosine Phosphatases/deficiency , Protein Tyrosine Phosphatases/metabolism , Protein-Tyrosine Kinases/metabolism , ras Proteins/metabolism , src-Family Kinases/metabolism , 3T3 Cells , Animals , CSK Tyrosine-Protein Kinase , Down-Regulation/physiology , Intercellular Signaling Peptides and Proteins , Intracellular Membranes/enzymology , Intracellular Signaling Peptides and Proteins , Membrane Proteins/metabolism , Mice , Mice, Knockout , Phospholipase C gamma , Phosphoproteins/metabolism , Phosphorylation , Protein Tyrosine Phosphatase, Non-Receptor Type 11 , Protein Tyrosine Phosphatases/genetics , Signal Transduction/physiology , Type C Phospholipases/metabolism , Tyrosine/metabolism
18.
Arthritis Res ; 4 Suppl 3: S189-96, 2002.
Article in English | MEDLINE | ID: mdl-12110139

ABSTRACT

Signals emanating from receptors of the tumor necrosis factor/nerve growth factor (TNF/NGF) family control practically all aspects of immune defense and, as such, constitute potential targets for therapeutic intervention through rational drug design. Indeed, arrest of these signals by blocking ligand-receptor interactions enables effective suppression of a variety of activities that are implicated in various pathologies, such as T and B lymphocyte activation and growth, inflammation, fibroblast proliferation, and cell death. To be therapeutically useful, however, inhibition of signaling should be restricted by determinants of specificity, at least to the same degree observed when blocking activation of individual receptors. In spite of their broad range of functions, receptors of the TNF/NGF family are known to activate just a few signaling pathways. Of these, the most extensively studied are the activation of the caspase protease cascade, which leads to cell death, and the activation of NF-kappaB (nuclear factor-kappaB) transcription factors through protein phosphorylation cascades. Until recently, most studies of the two pathways have solely focused on the core signaling complexes that are shared by the different receptors: death-inducing complexes containing the cysteine proteases caspase-8 and caspase-10, bound to the adapter protein MORT1/FADD (mediator of receptor-induced toxicity/Fas-associated DD protein), and the NF-kappaB-activating complex, composed of the protein kinases IKK1 (IkappaB kinase 1) and IKK2 (IkappaB kinase 2) and the regulatory subunit NEMO (NF-kappaB essential modulator; the 'IKK signalosome'). Knowledge has begun to emerge of additional molecules and mechanisms that affect these basic signaling complexes and impose specificity on their function.


Subject(s)
Apoptosis/immunology , NF-kappa B/metabolism , Nerve Growth Factor/metabolism , Signal Transduction/immunology , Tumor Necrosis Factor-alpha/metabolism , Animals , Caspases/metabolism , Humans , Nerve Growth Factor/immunology , Tumor Necrosis Factor-alpha/immunology
19.
Mol Cell Biol ; 22(12): 4062-72, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12024020

ABSTRACT

Receptor tyrosine kinases (RTKs) play distinct roles in multiple biological systems. Many RTKs transmit similar signals, raising questions about how specificity is achieved. One potential mechanism for RTK specificity is control of the magnitude and kinetics of activation of downstream pathways. We have found that the protein tyrosine phosphatase Shp2 regulates the strength and duration of phosphatidylinositol 3'-kinase (PI3K) activation in the epidermal growth factor (EGF) receptor signaling pathway. Shp2 mutant fibroblasts exhibit increased association of the p85 subunit of PI3K with the scaffolding adapter Gab1 compared to that for wild-type (WT) fibroblasts or Shp2 mutant cells reconstituted with WT Shp2. Far-Western analysis suggests increased phosphorylation of p85 binding sites on Gab1. Gab1-associated PI3K activity is increased and PI3K-dependent downstream signals are enhanced in Shp2 mutant cells following EGF stimulation. Analogous results are obtained in fibroblasts inducibly expressing dominant-negative Shp2. Our results suggest that, in addition to its role as a positive component of the Ras-Erk pathway, Shp2 negatively regulates EGF-dependent PI3K activation by dephosphorylating Gab1 p85 binding sites, thereby terminating a previously proposed Gab1-PI3K positive feedback loop. Activation of PI3K-dependent pathways following stimulation by other growth factors is unaffected or decreased in Shp2 mutant cells. Thus, Shp2 regulates the kinetics and magnitude of RTK signaling in a receptor-specific manner.


Subject(s)
Phosphatidylinositol 3-Kinases/metabolism , Protein Serine-Threonine Kinases , Protein Tyrosine Phosphatases/metabolism , Adaptor Proteins, Signal Transducing , Animals , Binding Sites , Cell Membrane/metabolism , Cells, Cultured , Enzyme Activation , Epidermal Growth Factor/metabolism , Epidermal Growth Factor/pharmacology , Insulin-Like Growth Factor I/pharmacology , Intracellular Signaling Peptides and Proteins , Mice , Mutation , Phosphatidylinositol 3-Kinases/genetics , Phosphoproteins/drug effects , Phosphoproteins/genetics , Phosphoproteins/metabolism , Platelet-Derived Growth Factor/pharmacology , Protein Transport/drug effects , Protein Tyrosine Phosphatase, Non-Receptor Type 11 , Protein Tyrosine Phosphatases/genetics , Proto-Oncogene Proteins/drug effects , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , Signal Transduction
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