Since the discovery of cyclins, the role of cell cycle regulators in the control of cell prolifer... more Since the discovery of cyclins, the role of cell cycle regulators in the control of cell proliferation has been extensively studied. It is clear that proliferation requires an adapted metabolic response of the cells; hence the regulation of cell cycle must be linked to metabolic control. While at a much slower pace, the impact that the activities of cell cycle regulators such as cyclins, cyclin dependent kinases or E2F factor, transcription factor have on cell metabolism are also being uncovered. Here we will focus on recent data implicating cell cycle regulators in metabolic control, with particular attention to studies performed using mouse models. Furthermore, we will discuss the possible relevance of these findings in the context of metabolic disorders such as obesity or diabetes.
Cells respond to stress by coordinating proliferative and metabolic pathways. Starvation restrict... more Cells respond to stress by coordinating proliferative and metabolic pathways. Starvation restricts cell proliferative (glycolytic) and activates energy productive (oxidative) pathways. Conversely, cell growth and proliferation require increased glycolytic and decreased oxidative metabolism levels 1 . E2F transcription factors regulate both proliferative and metabolic genes 2,3 . E2Fs have been implicated in the G1/S cell-cycle transition, DNA repair, apoptosis, development and differentiation 2-4 . In pancreatic β-cells, E2F1 gene regulation facilitated glucose-stimulated insulin secretion 5,6 . Moreover, mice lacking E2F1 (E2f1 −/− ) were resistant to diet-induced obesity 4 . Here, we show that E2F1 coordinates cellular responses by acting as a regulatory switch between cell proliferation and metabolism. In basal conditions, E2F1 repressed key genes that regulate energy homeostasis and mitochondrial functions in muscle and brown adipose tissue. Consequently, E2f1 −/− mice had a marked oxidative phenotype. An association between E2F1 and pRB was required for repression of genes implicated in oxidative metabolism. This repression was alleviated in a constitutively active CDK4 (CDK4 R24C ) mouse model or when adaptation to energy demand was required. Thus, E2F1 represents a metabolic switch from oxidative to glycolytic metabolism that responds to stressful conditions. E2f1 −/− mice are resistant to diet-induced obesity; thus, E2F transcription factor-1 (E2F1) may participate in the control of energy homeostasis 4 . E2f1 −/− mice consumed more oxygen (O 2 ) than E2f1 +/+ mice and had a lower respiratory exchange ratio , indicating an enhanced level of fatty acid oxidation. This may be secondary to higher brown adipose tissue (BAT) regulation of heat production. Indeed, E2f1 −/− rectal temperatures were increased in
The extraordinary importance of the services sector for the economy both in production and employ... more The extraordinary importance of the services sector for the economy both in production and employment cannot be denied. As a result, there have been both demands for an increase in Service Operations Management (SOM) research since the 1980s on the one hand, and, on the other, predictions that such an increase will take place [e.g.]. And yet, the amount of SOM research done in OM research has still only been minimal. This contradiction calls for an in-depth study of the state of affairs of SOM research, and we have conducted just such a study in 10 of the most relevant and representative outlets in the OM field, as well as in pipeline research (Proceedings of the POMS, DSI and EurOMA Conferences). Our results aim to provide answers to the following questions, amongst others: (1) Is greater importance now attached to SOM research within OM research? (2) What are the main topics of research? Are they the same topics that have been proposed in SOM research agendas? (3) What methods are used in SOM research? (4) What are the most commonly studied sectors of economic activities? (5) Are there any differences from OM research in terms of content and methods? Some of our findings show that although a growth in SOM research had been predicted in earlier studies, there is still only a minimal amount done (7.5% of OM research); seven topics command 61.5% of SOM research, which (with some exceptions) is consistent with SOM research agendas; there is more research done on strategic issues than on tactical/operational issues; models and simulations are still more common than empirical research, but trends point to a shift to the latter; the majority of research focuses on a specific sector, and three sectors account for 50% of the total; there is a clear connection between type of journal and type of research, research method and sector of activity. #
S6 kinase (S6K) deletion in metazoans causes small cell size, insulin hypersensitivity, and metab... more S6 kinase (S6K) deletion in metazoans causes small cell size, insulin hypersensitivity, and metabolic adaptations; however, the underlying molecular mechanisms are unclear. Here we show that S6K-deficient skeletal muscle cells have increased AMP and inorganic phosphate levels relative to ATP and phosphocreatine, causing AMP-activated protein kinase (AMPK) upregulation. Energy stress and muscle cell atrophy are specifically triggered by the S6K1 deletion, independent of S6K2 activity. Two known AMPK-dependent functions, mitochondrial biogenesis and fatty acid b-oxidation, are upregulated in S6K-deficient muscle cells, leading to a sharp depletion of lipid content, while glycogen stores are spared. Strikingly, AMPK inhibition in S6K-deficient cells restores cell growth and sensitivity to nutrient signals. These data indicate that S6K1 controls the energy state of the cell and the AMPK-dependent metabolic program, providing a mechanism for cell mass accumulation under high-calorie diet. Cell Metabolism AMPK Activation in S6K Null Cells Cell Metabolism 5, 476-487, June 2007 ª2007 Elsevier Inc. 477 Franç aise contre les Myopathies (to A. Sotiropoulos and M.P.), the Association Nationale de la Recherche (to B.V. and M.P.), and Telethon (to M.S.). S.A. is a recipient of a stipend from Region Ile-de-France and Cell Metabolism 5, 476-487,
Background: Human papillomavirus (HPV) infection is sexually transmitted, but the nature of the i... more Background: Human papillomavirus (HPV) infection is sexually transmitted, but the nature of the infection in males is poorly understood. We sought to identify determinants of HPV infection, acquisition, and persistence in 1,030 healthy military men in Mexico. Methods: From July 2000 to July 2003, trained interviewers administered a questionnaire, conducted a genital examination, and collected samples. The presence of multiple HPV types in genital cells from the urethra, urethral meatus, scrotum, penile shaft, and coronal sulcus was evaluated. At baseline 1,030 participants and after 1-year follow-up 336 individuals were sampled using a highly sensitive DNA reverse blot strip assay. Results: HPV prevalence was 44.6%; infection with high-risk types was observed in 34.8% participants and 51.1% were multiply infected. After 1-year follow-up, 165 men remained free of HPV, 68 cleared their infection, 45 acquired one, and 37 remained infected with the same HPV type. The period prevalence was 50.9%, the incidence rate was 17.9/1,000 men-months [95% confidence interval (95% CI), 13.0-23.9], clearance was 54%, and persistence was 29.4%. At baseline, the number of partners before age 20 years, a history of a sexually transmitted disease, and the presence of condilomas significantly increased the association with HPV infection. Having anal intercourse with males was associated with the risk of acquiring a HPV infection (odds ratio, 5.2; 95% CI, 1.2-23). The odds ratio for persistent infection was 0.10 (95% CI, 0-0.87) in men who reported being circumcised compared with those who did not. Conclusions: High-risk sexual behavior increases the risk of HPV infection in males, whereas circumcision may lower the risk
Since the discovery of cyclins, the role of cell cycle regulators in the control of cell prolifer... more Since the discovery of cyclins, the role of cell cycle regulators in the control of cell proliferation has been extensively studied. It is clear that proliferation requires an adapted metabolic response of the cells; hence the regulation of cell cycle must be linked to metabolic control. While at a much slower pace, the impact that the activities of cell cycle regulators such as cyclins, cyclin dependent kinases or E2F factor, transcription factor have on cell metabolism are also being uncovered. Here we will focus on recent data implicating cell cycle regulators in metabolic control, with particular attention to studies performed using mouse models. Furthermore, we will discuss the possible relevance of these findings in the context of metabolic disorders such as obesity or diabetes.
Cells respond to stress by coordinating proliferative and metabolic pathways. Starvation restrict... more Cells respond to stress by coordinating proliferative and metabolic pathways. Starvation restricts cell proliferative (glycolytic) and activates energy productive (oxidative) pathways. Conversely, cell growth and proliferation require increased glycolytic and decreased oxidative metabolism levels 1 . E2F transcription factors regulate both proliferative and metabolic genes 2,3 . E2Fs have been implicated in the G1/S cell-cycle transition, DNA repair, apoptosis, development and differentiation 2-4 . In pancreatic β-cells, E2F1 gene regulation facilitated glucose-stimulated insulin secretion 5,6 . Moreover, mice lacking E2F1 (E2f1 −/− ) were resistant to diet-induced obesity 4 . Here, we show that E2F1 coordinates cellular responses by acting as a regulatory switch between cell proliferation and metabolism. In basal conditions, E2F1 repressed key genes that regulate energy homeostasis and mitochondrial functions in muscle and brown adipose tissue. Consequently, E2f1 −/− mice had a marked oxidative phenotype. An association between E2F1 and pRB was required for repression of genes implicated in oxidative metabolism. This repression was alleviated in a constitutively active CDK4 (CDK4 R24C ) mouse model or when adaptation to energy demand was required. Thus, E2F1 represents a metabolic switch from oxidative to glycolytic metabolism that responds to stressful conditions. E2f1 −/− mice are resistant to diet-induced obesity; thus, E2F transcription factor-1 (E2F1) may participate in the control of energy homeostasis 4 . E2f1 −/− mice consumed more oxygen (O 2 ) than E2f1 +/+ mice and had a lower respiratory exchange ratio , indicating an enhanced level of fatty acid oxidation. This may be secondary to higher brown adipose tissue (BAT) regulation of heat production. Indeed, E2f1 −/− rectal temperatures were increased in
The extraordinary importance of the services sector for the economy both in production and employ... more The extraordinary importance of the services sector for the economy both in production and employment cannot be denied. As a result, there have been both demands for an increase in Service Operations Management (SOM) research since the 1980s on the one hand, and, on the other, predictions that such an increase will take place [e.g.]. And yet, the amount of SOM research done in OM research has still only been minimal. This contradiction calls for an in-depth study of the state of affairs of SOM research, and we have conducted just such a study in 10 of the most relevant and representative outlets in the OM field, as well as in pipeline research (Proceedings of the POMS, DSI and EurOMA Conferences). Our results aim to provide answers to the following questions, amongst others: (1) Is greater importance now attached to SOM research within OM research? (2) What are the main topics of research? Are they the same topics that have been proposed in SOM research agendas? (3) What methods are used in SOM research? (4) What are the most commonly studied sectors of economic activities? (5) Are there any differences from OM research in terms of content and methods? Some of our findings show that although a growth in SOM research had been predicted in earlier studies, there is still only a minimal amount done (7.5% of OM research); seven topics command 61.5% of SOM research, which (with some exceptions) is consistent with SOM research agendas; there is more research done on strategic issues than on tactical/operational issues; models and simulations are still more common than empirical research, but trends point to a shift to the latter; the majority of research focuses on a specific sector, and three sectors account for 50% of the total; there is a clear connection between type of journal and type of research, research method and sector of activity. #
S6 kinase (S6K) deletion in metazoans causes small cell size, insulin hypersensitivity, and metab... more S6 kinase (S6K) deletion in metazoans causes small cell size, insulin hypersensitivity, and metabolic adaptations; however, the underlying molecular mechanisms are unclear. Here we show that S6K-deficient skeletal muscle cells have increased AMP and inorganic phosphate levels relative to ATP and phosphocreatine, causing AMP-activated protein kinase (AMPK) upregulation. Energy stress and muscle cell atrophy are specifically triggered by the S6K1 deletion, independent of S6K2 activity. Two known AMPK-dependent functions, mitochondrial biogenesis and fatty acid b-oxidation, are upregulated in S6K-deficient muscle cells, leading to a sharp depletion of lipid content, while glycogen stores are spared. Strikingly, AMPK inhibition in S6K-deficient cells restores cell growth and sensitivity to nutrient signals. These data indicate that S6K1 controls the energy state of the cell and the AMPK-dependent metabolic program, providing a mechanism for cell mass accumulation under high-calorie diet. Cell Metabolism AMPK Activation in S6K Null Cells Cell Metabolism 5, 476-487, June 2007 ª2007 Elsevier Inc. 477 Franç aise contre les Myopathies (to A. Sotiropoulos and M.P.), the Association Nationale de la Recherche (to B.V. and M.P.), and Telethon (to M.S.). S.A. is a recipient of a stipend from Region Ile-de-France and Cell Metabolism 5, 476-487,
Background: Human papillomavirus (HPV) infection is sexually transmitted, but the nature of the i... more Background: Human papillomavirus (HPV) infection is sexually transmitted, but the nature of the infection in males is poorly understood. We sought to identify determinants of HPV infection, acquisition, and persistence in 1,030 healthy military men in Mexico. Methods: From July 2000 to July 2003, trained interviewers administered a questionnaire, conducted a genital examination, and collected samples. The presence of multiple HPV types in genital cells from the urethra, urethral meatus, scrotum, penile shaft, and coronal sulcus was evaluated. At baseline 1,030 participants and after 1-year follow-up 336 individuals were sampled using a highly sensitive DNA reverse blot strip assay. Results: HPV prevalence was 44.6%; infection with high-risk types was observed in 34.8% participants and 51.1% were multiply infected. After 1-year follow-up, 165 men remained free of HPV, 68 cleared their infection, 45 acquired one, and 37 remained infected with the same HPV type. The period prevalence was 50.9%, the incidence rate was 17.9/1,000 men-months [95% confidence interval (95% CI), 13.0-23.9], clearance was 54%, and persistence was 29.4%. At baseline, the number of partners before age 20 years, a history of a sexually transmitted disease, and the presence of condilomas significantly increased the association with HPV infection. Having anal intercourse with males was associated with the risk of acquiring a HPV infection (odds ratio, 5.2; 95% CI, 1.2-23). The odds ratio for persistent infection was 0.10 (95% CI, 0-0.87) in men who reported being circumcised compared with those who did not. Conclusions: High-risk sexual behavior increases the risk of HPV infection in males, whereas circumcision may lower the risk
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