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The neighborhood environment has the potential to influence personal choices to be physically active. Little information is available in national populations of the relationship between environmental supports for physical activity (PA) and PA behaviors. PURPOSE To identify the associations between self-report of neighborhood environmental features for PA and individual PA behaviors in US adults. METHODS 10,455 adults (4,437 men 6,018 women) responded to the National PA and Weight Loss Survey, a random digit dial survey of US households conducted Sept to Dec 2002. As part of a larger survey, respondents reported the presence or absence of neighborhood features (i.e., shops and transit stops within walking distance from home, sidewalks on most streets, places to bicycle, low-cost or free recreational facilities, four-way traffic intersections, and crime rate), their individual PA levels, and demographic data. PA was obtained from the IPAQ as d/wk and min/day of moderate, vigorous, and walking PA and categorized into 3 groups: Health Enhancing PA (> 3 days vig PA and >1,500 MET-min/wk mod-vig-walk PA or >5 d/wk mod-vig-walk PA and >3,000 MET-min/wk of mod-vig-walk PA), Minimally Active (> 3 d/wk vig PA >20 min/d or >5 d/wk mod PA >30 min/d or >5 d/wk walk >30 min/d or >5 d/w mod-vig-walk and 600 MET-min/wk of mod-vig-walk PA), or Inactive (less than above). Logistic regression models were used to calculate crude and adjusted odds ratios (OR, 95% CI) for the likelihood of a specified level of PA given the presence of an environmental support for PA. OR's were adjusted for sex, age, race, and education. RESULTS Based on adjusted OR's, those with shops within walking distance of home (OR = 1.16, CI = 1.02, 1.31), places to bicycle in the neighborhood (OR = 1.32, CI = 1.16, 1.50), free/low cost recreation facilities OR = 1.25, CI = 1.10, 1.42), and lower neighborhood crime (OR = 1.14, CI = 1.01, 1.32) were more likely to have Health Enhancing PA levels than those without the supports. Also, those with a transit stop within 10–15 min walk from home (OR = 1.19, CI = 1.03, 1.37), places to bicycle in the neighborhood (OR = 1.31, CI = 1.14, 1.51), and free/low cost recreation facilities (OR 1.30, CI = 1.12, 1.50) were more likely to be Minimally Active than those without supports. Few differences in responses were observed by sex, age, and race. CONCLUSIONS Environments supportive of purposeful walking/cycling, having free/low cost recreational spaces, and low neighborhood crime are associated with higher levels of PA. These national results support previous findings and suggest environmental changes that could increase PA. Supported by CDC Cooperative Agreement, SIP 20-01, U48/CCU409664.
A potential link between inflammation and cancer has been suspected for over a century, but the exact molecular mechanisms connecting the two remained nebulous. We proposed that NF-kappaB transcription factors regulated via the IkappaB kinase (IKK) complex play a critical role in coupling inflammation and cancer and have set out to test this hypothesis in mouse models of cancer. Using mice bearing mutations in the genes coding for the IKKbeta and IKKalpha catalytic subunits we obtained evidence supporting a critical role for IKKbeta in tumor promotion and more recently identified the involvement of IKKalpha in metastatogenesis. Whereas the major pro-tumorigenic function of IKKbeta is mediated via NF-kappaB, the pro-metastatic function of IKKalpha is NF-kappaB-independent. In addition to illustrating the critical roles of the two IKK molecules in linking inflammation and cancer and providing an explanation for increased cancer risk in response to persistent infections and inflammation, these results also identify new targets for development of novel anti-cancer therapies and preventive strategies. Instead of targeting the cancer cell itself, as done by conventional anti-cancer drugs, the new therapeutics will target processes that occur within inflammatory cells that are essential for cancer development and progression. Unlike cancer cells, inflammatory cells retain a normal and stable genome and therefore are unlikely to become genetically resistant to therapeutic intervention.
Click to increase image sizeClick to decrease image sizeKey Words: determinantsexercisesocial supportyouth
NF-kappaB (nuclear factor-kappaB) is a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-kappaB is found in essentially all cell types and is involved in activation of an exceptionally large number of genes in response to infections, inflammation, and other stressful situations requiring rapid reprogramming of gene expression. NF-kappaB is normally sequestered in the cytoplasm of nonstimulated cells and consequently must be translocated into the nucleus to function. The subcellular location of NF-kappaB is controlled by a family of inhibitory proteins, IkappaBs, which bind NF-kappaB and mask its nuclear localization signal, thereby preventing nuclear uptake. Exposure of cells to a variety of extracellular stimuli leads to the rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of IkappaB, which frees NF-kappaB to translocate to the nucleus where it regulates gene transcription. NF-kappaB activation represents a paradigm for controlling the function of a regulatory protein via ubiquitination-dependent proteolysis, as an integral part of a phosphorylationbased signaling cascade. Recently, considerable progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1. The multisubunit IkappaB kinase (IKK) responsible for inducible IkappaB phosphorylation is the point of convergence for most NF-kappaB-activating stimuli. IKK contains two catalytic subunits, IKKalpha and IKKbeta, both of which are able to correctly phosphorylate IkappaB. Gene knockout studies have shed light on the very different physiological functions of IKKalpha and IKKbeta. After phosphorylation, the IKK phosphoacceptor sites on IkappaB serve as an essential part of a specific recognition site for E3RS(IkappaB/beta-TrCP), an SCF-type E3 ubiquitin ligase, thereby explaining how IKK controls IkappaB ubiquitination and degradation. A variety of other signaling events, including phosphorylation of NF-kappaB, hyperphosphorylation of IKK, induction of IkappaB synthesis, and the processing of NF-kappaB precursors, provide additional mechanisms that modulate the level and duration of NF-kappaB activity.
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Cellular calcium (Ca2+) and the Ca2+-binding protein calmodulin (CaM) regulate the activities of Ca2+/CaM-dependent protein kinases and protein phosphatase 2B (calcineurin). Functional interactions between CaM kinases and mitogen-activated protein (MAP) kinases were described. In this report, we describe cross-talk between calcineurin and mitogen-activated protein kinase signaling. Calcineurin was found to specifically down-regulate the transcriptional activity of transcription factor Elk1, following stimulation of this activity by the ERK, Jun N-terminal kinase, or p38 MAP kinase pathways. Expression of constitutively activated calcineurin or activation of endogenous calcineurin by Ca2+ ionophore decreased the phosphorylation of Elk1 at sites that positively regulate its transcriptional activity. Calcineurin specifically dephosphorylates Elk1 at phosphoserine 383, a site whose phosphorylation by MAP kinases makes a critical contribution to the enhanced transcriptional activity of Elk1. The cross-talk between calcineurin and MAP kinases is of physiological significance as low doses of Ca2+ ionophore which by themselves are insufficient for c-fos induction can actually inhibit induction of c-fos expression by activators of MAP kinases. Thus through the effect of calcineurin on Elk1 phosphorylation, Ca2+ can have a negative effect on expression of Elk1 target genes. This mechanism explains why different levels of intracellular Ca2+ can result in very different effects on gene expression. Cellular calcium (Ca2+) and the Ca2+-binding protein calmodulin (CaM) regulate the activities of Ca2+/CaM-dependent protein kinases and protein phosphatase 2B (calcineurin). Functional interactions between CaM kinases and mitogen-activated protein (MAP) kinases were described. In this report, we describe cross-talk between calcineurin and mitogen-activated protein kinase signaling. Calcineurin was found to specifically down-regulate the transcriptional activity of transcription factor Elk1, following stimulation of this activity by the ERK, Jun N-terminal kinase, or p38 MAP kinase pathways. Expression of constitutively activated calcineurin or activation of endogenous calcineurin by Ca2+ ionophore decreased the phosphorylation of Elk1 at sites that positively regulate its transcriptional activity. Calcineurin specifically dephosphorylates Elk1 at phosphoserine 383, a site whose phosphorylation by MAP kinases makes a critical contribution to the enhanced transcriptional activity of Elk1. The cross-talk between calcineurin and MAP kinases is of physiological significance as low doses of Ca2+ ionophore which by themselves are insufficient for c-fos induction can actually inhibit induction of c-fos expression by activators of MAP kinases. Thus through the effect of calcineurin on Elk1 phosphorylation, Ca2+ can have a negative effect on expression of Elk1 target genes. This mechanism explains why different levels of intracellular Ca2+ can result in very different effects on gene expression. The second messenger Ca2+ plays a critical regulatory role in a variety of physiological processes in many different cell types (1Bading H. Hardingham G.E. Johnson C.M. Chawla S. Biochem. Biophys. Res. Commun. 1997; 236: 541-543Crossref PubMed Scopus (76) Google Scholar, 2Malviya A.N. Rogue P.J. Cell. 1998; 92: 17-23Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar). One of the most important mediators of Ca2+ signaling is the Ca2+-binding protein, calmodulin (CaM) 1The abbreviations used are: CaM, calmodulin; CaM-K, Ca2+/CaM-dependent protein kinases; MAP, mitogen-activated protein; MAPK, MAP kinase; CsA, cyclosporin A; CREB, cAMP-responsive element binding protein; SRF, serum response factor; GST, glutathione S-transferase; WCE, whole cell extract; PAGE, polyacrylamide gel electrophoresis; HA, hemagglutinin; NE, nuclear extract; TCF, ternary complex factors; RT-PCR, reverse transcriptase-polymerase chain reaction; JNK, Jun N-terminal kinase; CRE, cAMP response element; MEK, MAPK kinases; ATF, activating transcription factor; EGF, epidermal growth factor; SRE, serum response element. (3Vogel H.J. Zhang M. Mol. Cell. Biochem. 1995; 149/150: 3-15Crossref Scopus (71) Google Scholar). The Ca2+-CaM complex binds to and modulates the activities of multiple key signal-transducing enzymes, including Ca2+/CaM-dependent protein kinases (CaM-K) (4Tokumitsu H. Soderling T.R. J. Biol. Chem. 1996; 271: 5617-5622Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar,5Wayman G.A. Tokumitsu H. Soderling T.R. J. Biol. Chem. 1997; 272: 16073-16076Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar) and the Ca2+/CaM-dependent protein serine/threonine phosphatase calcineurin (6Guerini D. Biochem. Biophys. Res. Commun. 1997; 235: 271-275Crossref PubMed Scopus (141) Google Scholar, 7Lohse D.L. Denu J.M. Dixon J.E. Structure. 1995; 3: 987-990Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). The CaM kinases have several substrates involved in transcriptional control, such as CREB (cAMP-responsive element binding protein) (8Cruzalegui F.H. Means A.R. J. Biol. 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Besides a catalytic domain, which is conserved among members of the protein phosphatase family, which includes protein phosphatases 1 and 2a and bacteriophage λ phosphatase (7Lohse D.L. Denu J.M. Dixon J.E. Structure. 1995; 3: 987-990Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar), CnA contains a C-terminal autoinhibitory domain as well as CaM and CnB binding domains (12Villafranca J.E. Kissinger C.R. Parge H.E. Curr. Opin. Biotechnol. 1996; 7: 397-402Crossref PubMed Scopus (29) Google Scholar). Ca2+/CaM binding activates CnA by relieving autoinhibition, which, in the absence of Ca2+/calmodulin, blocks access of substrates to the catalytic site (13Kissinger C.R. Parge H.E. Knighton D.R. Lewis C.T. Pelletier L.A. Tempczyk A. Kalish K.D. Showalter R.E. Moomaw E.W. Nature. 1995; 378: 641-644Crossref PubMed Scopus (707) Google Scholar). A truncation that removes the autoinhibitory domain and a portion of the CaM binding region results in a constitutively active form (ΔCaM-AI) that no longer requires Ca2+ (14Clipstone N.A. Crabtree G.R. Ann. N. Y. Acad. Sci. 1993; 696: 20-30Crossref PubMed Scopus (115) Google Scholar, 15O'Keefe S.J. Tamura J. Kincaid R.L. Tocci M.J. O'Neill E.A. Nature. 1992; 357: 692-694Crossref PubMed Scopus (823) Google Scholar). Calcineurin is a target for immunosuppressive drugs, such as cyclosporin A (CsA) and FK506 (16Stoddard B.L. Flick K.E. Curr. Opin. Struct. Biol. 1996; 6: 770-775Crossref PubMed Scopus (22) Google Scholar). These drugs inhibit calcineurin activity after forming complexes with cytoplasmic immunophilins, cyclophilins, and FK506-binding proteins, respectively (16Stoddard B.L. Flick K.E. Curr. Opin. Struct. Biol. 1996; 6: 770-775Crossref PubMed Scopus (22) Google Scholar). These immunophilin-immunosuppressant complexes bind calcineurin and inhibit its function by sterically hindering the access of substrates to the catalytic site (13Kissinger C.R. Parge H.E. Knighton D.R. Lewis C.T. Pelletier L.A. Tempczyk A. Kalish K.D. Showalter R.E. Moomaw E.W. Nature. 1995; 378: 641-644Crossref PubMed Scopus (707) Google Scholar, 17Griffith J.P. Kim J.L. Kim E.E. Sintchak M.D. Thomson J.A. Fitzgibbon M.J. Fleming M.A. Caron P.R. Hsiao K. Navia M.A. Cell. 1995; 82: 507-522Abstract Full Text PDF PubMed Scopus (783) Google Scholar). An increasing number of calcineurin-dependent cellular processes were identified through the use of these specific inhibitors and by expression of the constitutively active mutant (ΔCaM-AI) (6Guerini D. Biochem. Biophys. Res. Commun. 1997; 235: 271-275Crossref PubMed Scopus (141) Google Scholar). The most well characterized functions of calcineurin are during T cell activation (18Crabtree G.R. Clipstone N.A. Annu. Rev. 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H. Johnson M. 1995; 268: PubMed Scopus Google Scholar, J. M. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar). The was with and of protein and at for The was with and kinase with phosphatase protein was as J. M. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar). of protein was with the in kinase with of of in a was at for of kinase with were and the was at for the was with of and the was at for with kinase 1 the were with glutathione in kinase The were with was with the chain was with the to the of was The of the were and 1 of was The of the were and The were on gel and with The of the was by A was by the with a of The substrates were with calcineurin and calmodulin in phosphatase 1 1 serum The were at for and by of and were by and the results were by and by specifically the effect of calcineurin on different MAPK the constitutively CnA mutant (ΔCaM-AI) was with expression a constitutively active form of the of a protein between the binding domain and the activation domain to a whose contains sites In the of transcriptional activity by was to on phosphorylation of the activation domain at and A. A. H. Johnson M. 1995; 268: PubMed Scopus Google Scholar, A. A. M. Johnson M. 1994; PubMed Scopus Google Scholar). of with no effect on stimulation of activity the effect of on the of p38 to we used activated expression H. J. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) to the activity of a protein, which contains the activation The of activity by was by of the effect on a which contains the Elk1 activation domain J. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar), was with the with or expression for activated A. A. M. Johnson M. 1994; PubMed Scopus Google Scholar). of enhanced the of to expression of the This stimulation was of Upon such as with epidermal growth factor or expression of constitutively active the are activated through phosphorylation at the conserved and by the J.L. Nature. PubMed Scopus Google Scholar). the effect of on activation by with expression for the with specific for activated J.L. Nature. PubMed Scopus Google Scholar) as phosphorylation was by This phosphorylation was of activity was by kinase was and the were with and in kinase activity by with no effect on the activation of and its to in factor Elk1 is by the by the and p38 Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar). phosphorylation of sites in its C-terminal activation domain, of these kinases Elk1 transcriptional activity Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar). to at which expression of activated calcineurin the stimulation of Elk1 the was with expression in the absence or of of enhanced transcriptional activity by with in a in this stimulation expression of levels of can or p38 effect on activity A. A. M. Johnson M. 1994; PubMed Scopus Google Scholar, Y. M. Genes Dev. 1998; PubMed Scopus Google Scholar), we used specific and and p38 J. M. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar) and H. J. J. Biol. 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Sci. 1994; Google Scholar) no effect on the of Elk1 of the effect on Elk1 or calcineurin CnA or CnB expression. we activation of calcineurin effect on well characterized Elk1 target is well that elevated intracellular Ca2+ can through CaM kinase activation which CREB and transcription factors that bind to a in the c-fos M.A. A. 1995; PubMed Scopus Google Scholar). therefore to a to calcineurin activity activating CaM kinases. calcineurin is to Ca2+ CaM kinases Res. PubMed Scopus Google Scholar), we the of for c-fos in of with can with 1 or no therefore with 1 can c-fos induction by that intracellular a of the and p38 MAP kinase M. M. J. 1995; 14: PubMed Scopus Google Scholar), as the c-fos transcription This induction was by with 1 this effect is by by cyclosporin A. with cyclosporin A the of we the effect of these on the phosphorylation of endogenous Elk1. The endogenous Elk1 protein was by on and its phosphorylation by with the effect of the different on c-fos expression very well with effect on Elk1 phosphorylation at the of Elk1 in these was nuclear is very that the in the calcineurin is a serine/threonine protein phosphatase and its expression or activation a effect on the phosphorylation of Elk1 at in we Elk1 is a for The used in this was a protein that was in by in calcineurin or The substrates were by phosphorylation of the with activated Calcineurin Elk1 and to the transcription factor and are substrates for D. H. M. M. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar, M. N. M. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). calcineurin was with of of the was results were of was by with specific to at with the Elk1 that with calcineurin the by of through Calcineurin is a protein phosphatase that is activated binding of Ca2+-CaM (6Guerini D. Biochem. Biophys. Res. Commun. 1997; 235: 271-275Crossref PubMed Scopus (141) Google Scholar, H. S. T. M. Mol. 1997; PubMed Scopus Google Scholar). the of calcineurin in and gene have in and cell types G. Y. M. J. 1998; PubMed Scopus Google Scholar, J. J. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, M. Cell. 1998; 92: Full Text Full Text PDF PubMed Scopus Google Scholar). The functions of calcineurin in cell types are The calcineurin to a transcription Elk1, which as a target for MAPK and plays important role in induction of gene found that activation of calcineurin can inhibit the stimulation of Elk1 transcriptional activity by MAPK MAPK activation is to by specific MAPK such as which the activating sites the of P.S. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). In the the target for the phosphatase is a specific MAPK the MAPK is that MAPK phosphatases and in in of the calcineurin gene results in a growth T. H. M. T. J. 1998; PubMed Scopus Google Scholar). A gene which a MAPK this T. H. M. T. J. 1998; PubMed Scopus Google Scholar). the mechanism for this is in of results is that calcineurin dephosphorylates a MAPK involved in of In the absence of the in its which One to reverse this effect is to inhibit the activity of the MAPK for the phosphorylation Elk1 is the most of the characterized as transcription factors involved in induction of c-fos and members of its by M.A. A. 1995; PubMed Scopus Google Scholar). The are transcription which with the Jun to form P. M. Biophys. PubMed Scopus Google Scholar). The are involved in the of many target genes. of the c-fos gene is activated by a variety of such as and growth and J. 1995; 14: PubMed Scopus Google M.A. A. 1995; PubMed Scopus Google Scholar). The of Elk1 by to the of c-fos and Ca2+ signaling in The c-fos contains the and the M.A. A. 1995; PubMed Scopus Google Scholar). The response is by the of The activity of CREB is by phosphorylation at which can by a number of protein kinases including the protein kinase A P. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar), the Ca2+/CaM-dependent CaM kinases M. M.A. Greenberg M.E. PubMed Scopus Google Scholar), protein kinase H. J. 1995; Google Scholar), and growth kinases M. J. J. 1997; PubMed Google Scholar). The activity of is by and phosphorylation at S. D. 1995; PubMed Scopus Google Scholar), the that the activity of are This is the why calcineurin the induction of c-fos transcription by can by activated and p38 and is by calcineurin The is a binding site for the and the M.A. A. 1995; PubMed Scopus Google Scholar). were including Elk1 J. 1995; 14: PubMed Scopus Google Scholar), S. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar), and A. A. P. Genes Dev. 1994; 8: PubMed Scopus Google Scholar). The to the family, characterized by a conserved binding domain Y. P.R. J. Biochem. 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PubMed Scopus Google Scholar). a in intracellular Ca2+ have a negative effect on c-fos transcription through activation of a in c-fos transcription through activation of and as in of with 1 is for induction of c-fos transcription intracellular Ca2+ to a for CaM kinase that of Ca2+ is for of c-fos induction by that MAPK signaling is for activation of as by the of Elk1. a mechanism the regulatory of Ca2+ In to its regulatory effect on Elk1 at the c-fos or calcineurin in the Calcineurin is to a cytoplasmic protein (6Guerini D. Biochem. Biophys. Res. Commun. 1997; 235: 271-275Crossref PubMed Scopus (141) Google Scholar). no nuclear A. J. A. Acad. Sci. S. A. 1996; PubMed Scopus Google Scholar). in the of activated T A. J. A. Acad. Sci. S. A. 1996; PubMed Scopus Google Scholar). was that after calcineurin dephosphorylates to the by of its with this transcription factor A. J. A. Acad. Sci. S. A. 1996; PubMed Scopus Google Scholar). 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HeLa cells in culture synthesize metallothionein. To investigate the effects of glucocorticoids on metallothionein synthesis we adapted HeLa cells to growth in a defined medium lacking hydrocortisone. In this defined medium, containing 1.5 x 10(-6)M Zn2+, dexamethasone (10(-6)M) caused a five- to sixfold increase in the synthesis of metallothionein. Progesterone (10(-5)M), a known antagonist of glucocorticoids, inhibited this response by 50 percent.
Over the past forty years various changes in the U.S. "built environment" have promoted sedentary lifestyles and less healthful diets. James Sallis and Karen Glanz investigate whether these changes have had a direct effect on childhood obesity and whether improvements to encourage more physical activity and more healthful diets are likely to lower rates of childhood obesity. Researchers, say Sallis and Glanz, have found many links between the built environment and children's physical activity, but they have yet to find conclusive evidence that aspects of the built environment promote obesity. For example, certain development patterns, such as a lack of sidewalks, long distances to schools, and the need to cross busy streets, discourage walking and biking to school. Eliminating such barriers can increase rates of active commuting. But researchers cannot yet prove that more active commuting would reduce rates of obesity. Sallis and Glanz note that recent changes in the nutrition environment, including greater reliance on convenience foods and fast foods, a lack of access to fruits and vegetables, and expanding portion sizes, are also widely believed to contribute to the epidemic of childhood obesity. But again, conclusive evidence that changes in the nutrition environment will reduce rates of obesity does not yet exist. Research into the link between the built environment and childhood obesity is still in its infancy. Analysts do not know whether changes in the built environment have increased rates of obesity or whether improvements to the built environment will decrease them. Nevertheless, say Sallis and Glanz, the policy implications are clear. People who have access to safe places to be active, neighborhoods that are walkable, and local markets that offer healthful food are likely to be more active and to eat more healthful food-two types of behavior that can lead to good health and may help avoid obesity.
