Publications

The primary aim was to examine the effects of a physical activity and nutrition intervention on Body Dissatisfaction, Drive for Thinness, and Weight Concerns in pre-adolescents. Eighty-four 10–12 years old were studied as part of a larger trial of a family-based physical activity and nutrition intervention. Forty-nine children participated in the 8-week intervention (35 in control group) and completed Body Dissatisfaction, Drive for Thinness, and Weight Concerns measures at baseline and post-test. Participants in both groups showed positive but non-significant changes in body image and Drive for Thinness following the trial, but there were no significant between group differences. This was the first study to examine the effects of a physical activity and nutrition intervention on body image and related variables in pre-adolescents. Body Dissatisfaction, Drive for Thinness, and Weight Concerns were not positively or negatively influenced by the intervention.

International groups have recommended environmental and policy changes as central strategies in efforts to increase physical activity worldwide. Research is needed to guide policy actions, but built environment and physical activity is a relatively new research topic that initially was conducted in just a few countries. The generalizability of findings cannot be assumed across countries with distinct environments and cultures. Initial findings, mainly from studies of North America and Australia, indicated that walkable community designs were related to active transportation, and proximity to parks was related to active recreation. In recent years, those general findings have mainly been supported in studies from Japan, Europe, and South America. Evidence to date indicates there may be generalizable principles about how to build communities that facilitate people being active for transportation and recreation purposes. Country-specific studies are needed to inform local decision making in city planning, transportation, parks, education, and health departments/ministries. Coordinated international studies are needed to guide international actions to reduce the epidemics of physical inactivity and chronic diseases.

Identifying correlates of children's television (TV) watching could help identify strategies to reduce children's TV watching and impact children's weight status. Children's TV time and home environment factors were assessed longitudinally among 169 families with children followed from 6 to 12 years of age. TV watching increased with age, as did the number of in-home TVs and the presence of videocassette recorders (VCRs), the frequency of meal eating while watching TV, and the percentage of children with bedroom TVs. Greater meal eating while watching TV was consistently related to overall TV watching and increases in TV watching over time. The number of in-home TVs and the presence of a bedroom TV were less consistent correlates. TV watching was related to weight status when children were younger, and when children were older, more than 2 hours of TV daily was a risk factor for higher weight. Modifying TV access, particularly by reducing the frequency of meals eaten while watching TV, could promote lower children's TV watching and adiposity.

Purpose. Neighborhood built environments are related to obesity and physical activity (PA), but inconsistently to sedentary behaviors. This study investigated the mediating effects of PA and sedentary time on the associations of neighborhood environmental factors and body mass index (BMI) among Nigerian adults. Design. The study design was cross-sectional. Setting. The study setting was metropolitan Maiduguri, Nigeria. Subjects. Nigerian adults (n = 1411) were randomly selected from diverse neighborhoods and had complete data (43.1% women, 33.8% overweight or obese). Measures. PA, sedentary time, and 16 perceived neighborhood environmental factors were measured using Nigerian adaptations of validated international questionnaires. Outcomes were measured BMI and interviewer-led self-reports of moderate to vigorous PA, walking, total PA, and sitting time. Analysis. The product-of-coefficient test using generalized linear models was used to assess the mediating effects of outcomes on the associations between environmental factors and BMI. Results. Walking and total PA significantly mediated the association between BMI and perception of higher residential density (αβ = –.025 and –.037, respectively), absence of garbage (αβ = –.046 and –.076, respectively), and more safety from crime at night (αβ = –.044 and –.083, respectively). In addition, walking, moderate to vigorous PA, and total PA significantly mediated the association between BMI and perception of better aesthetics (αβ = –.035, –.022, and –.071, respectively). Sedentary time was not a significant mediator of any associations between environmental factors and BMI. Conclusion. The association of several neighborhood environmental variables with BMI was partially mediated by PA in Nigerian adults. Including questions on specific types of sedentary behaviors in future prospective studies may improve understanding of the relative influence of sedentary behavior and physical activity on obesity control and prevention among sub-Saharan African adults.

No abstract is provided for this article.

PURPOSE Neighborhood walkability, characterized by mixed land use, street connectivity, and residential density, has been found to be related to overall physical activity. In previous analyses, this association was significant in high income adults, but not in low income adults. The purpose of the present study was to test the hypothesis that car availability moderated the relation between neighborhood walkability and physical activity. METHODS A random sample of adults was recruited from neighborhoods in Seattle and King County, WA that varied by walkability and income. Participants reported the number of operating motor vehicles in their households. Physical activity was measured by 7 days of monitoring with Actigraph accelerometers, and mean daily minutes of moderate-to-vigorous physical activity (MVPA) were computed. A neighborhood walkability index was calculated for a 1-km radius around each participant's home based on the street network using Geographic Information Systems. Multiple regressions were conducted separately for low- and high-income participants to explain MVPA, controlling for age and sex. RESULTS Of the 624 low-income participants, 8.5% had no car. Of the 659 high-income participants, 1.8% had no car. The median of cars per household for each group was 2.0. Interactions between walkability and car availability were not significant for low- (p<.15) or high-income (p<.46) participants. In regressions without interactions for the high-income group, walkability explained 3.6% of the variance (p<.001), but car ownership explained only .003% (p<.90). Results for the low-income group showed walkability explained 1.2% of the variance (p<.01), and there was a trend for car ownership to be negatively related to MVPA (.006% of variance, p<.06). CONCLUSIONS The hypothesized moderating effect of car availability on the relation between walkability and MVPA was not supported for low- or high-income adults. However, when car availability was included in the regression model for lowincome adults, it was marginally significant, indicating further study of this variable is warranted. In contrast to previous analyses, when car availiability was in the model for low-income adults, walkability was significantly related to MVPA. Different patterns of associations between environmental variables and MVPA may be operating for different population subgroups. Supported by NIH grant HL67350.

Native Hawaiian and Pacific Islander (NHPI) people are an understudied population that demonstrates high obesity rates and low physical activity levels. This study's aim was to examine possible correlates of physical activity in NHPI adults. Height and weight were recorded in N=100 NHPIs (46.9±5.4 years; 56% males) following completion of an anonymous questionnaire addressing health behaviors (physical activity, smoking, diet), psychosocial characteristics (social support, barriers, stage of change), neighborhood environment attributes, and knowledge of physical activity recommendations. This study sample demonstrated low physical activity (20% met recommendations) and fruit and vegetable (F&V) consumption (1% met recommendations), and a high prevalence of overweight or obesity (94%). After adjusting for gender and education, F&V intake was the only significant correlate of physical activity (p<.001). Common correlates of physical activity did not generalize to NHPIs. Further investigations of culturally-specific correlates are needed so that physical activity interventions can be culturally tailored for NHPIs.

On the eve of the 2012 summer Olympic Games, the first Lancet Series on physical activity established that physical inactivity was a global pandemic, and global public health action was urgently needed. The present paper summarises progress on the topics covered in the first Series. In the past 4 years, more countries have been monitoring the prevalence of physical inactivity, although evidence of any improvements in prevalence is still scarce. According to emerging evidence on brain health, physical inactivity accounts for about 3·8% of cases of dementia worldwide. An increase in research on the correlates of physical activity in low-income and middle-income countries (LMICs) is providing a better evidence base for development of context-relevant interventions. A finding specific to LMICs was that physical inactivity was higher in urban (vs rural) residents, which is a cause for concern because of the global trends toward urbanisation. A small but increasing number of intervention studies from LMICs provide initial evidence that community-based interventions can be effective. Although about 80% of countries reported having national physical activity policies or plans, such policies were operational in only about 56% of countries. There are important barriers to policy implementation that must be overcome before progress in increasing physical activity can be expected. Despite signs of progress, efforts to improve physical activity surveillance, research, capacity for intervention, and policy implementation are needed, especially among LMICs.

Introduction In the past 15 years, researchers, practitioners, and community residents and leaders have become increasingly interested in associations among built environments and physical activity, diet, and obesity. Numerous tools to measure activity and food environments have been developed but vary in quality and usability. Future progress depends on aligning these tools with new communication technology and increasing their utility for planning and policy. Methods The Built Environment Assessment Training Institute Think Thank was held in July 2013. Expert participants discussed priorities, gaps, and promising opportunities to advance the science and practice of measuring obesity-related built environments. Participants proposed and voted on recommended future directions in two categories: “big ideas” and additional recommendations. Results Recommendations for the first “big idea” involve developing new, simplified built environment assessment tools and deploying them through online trainings and easily accessible web-based apps. Future iterations of the tools would link to databases of key locations (e.g., parks, food stores); have built-in scoring and analysis; and provide clear, simple feedback to users. A second “big idea” addresses dissemination of results from built environment assessments and translation into policies including land use and food access planning. Additional recommendations include (1) improving multidisciplinary collaborations; (2) engaging stakeholders across sectors; (3) centralized data resource centers; (4) increased use of emerging technologies to communicate findings; and (5) advocating for expanded funding for measurement development, training, and dissemination. Conclusions Implementing these recommendations is likely to improve the quality of built environment measures and expand their use in research and practice.

Objective. Little is known about the types of physical activity (PA) in which adolescent girls participate. Understanding this, along with examining specific psychosocial correlates of PA, may help guide the development of effective interventions to prevent the decline in PA in female youth. Methods. 2791 sixth grade girls participating in the Trial of Activity for Adolescent Girls from six geographical locations completed surveys assessing participation in sports teams and activity classes/lessons in and out of school, self-efficacy for PA, PA enjoyment, physical education (PE) enjoyment, and perceived school climate for girls' PA (data collection: January–May 2003). Correlates of girls' participation in structured PA and sociodemographic differences were explored. Results. 89.5% of girls participated in structured PA: 39% at school and 86% outside of school. Across race/ethnicity, most reported activities were basketball (44%), cheerleading/dance (41%), and swimming (39%). Controlling for socioeconomic status, geographical location, and race/ethnicity, girls with a higher self-efficacy (OR=3.44, CI=1.72–6.92) and higher enjoyment of PE class (OR=1.97, CI=1.25–3.120) were more likely to participate in structured PA. PA enjoyment and perceived school climate for girls' PA were not associated with participation in structured PA. Conclusion. Interventions that increase self-efficacy and enjoyment of PE could result in greater participation in structured PA and higher overall PA levels among adolescent girls.

No abstract is provided for this article.

Physical inactivity is an important contributor to non-communicable diseases in countries of high income, and increasingly so in those of low and middle income. Understanding why people are physically active or inactive contributes to evidence-based planning of public health interventions, because eff ective programmes will target factors known to cause inactivity. Research into correlates (factors associated with activity) or determinants (those with a causal relationship) has burgeoned in the past two decades, but has mostly focused on individual-level factors in high-income countries. It has shown that age, sex, health status, self-effi cacy, and motivation are associated with physical activity. Ecological models take a broad view of health behaviour causation, with the social and physical environment included as contributors to physical inactivity, particularly those outside the health sector, such as urban planning, transportation systems, and parks and trails. New areas of determinants research have identifi ed genetic factors contributing to the propensity to be physically active, and evolutionary factors and obesity that might predispose to inactivity, and have explored the longitudinal tracking of physical activity throughout life. An understanding of correlates and determinants, especially in countries of low and middle income, could reduce the eff ect of future epidemics of inactivity and contribute to eff ective global prevention of non-communicable diseases.

AP-1 is a sequence-specific transcriptional activator composed of members of the Jun and Fos families (for review see Ref. 1Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3256) Google Scholar). These proteins, which belong to the bZIP group of DNA binding proteins (for review see Ref. 2Johnson P.F. McKnight S.L. Annu. Rev. Biochem. 1989; 58: 799-839Crossref PubMed Scopus (829) Google Scholar), associate to form a variety of homo- and heterodimers that bind to a common site(1Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3256) Google Scholar). First identified by its role in human metallothionein IIA gene regulation(3Lee W. Haslinger A. Karin M. Tjian R. Nature. 1987; 325: 368-372Crossref PubMed Scopus (484) Google Scholar), AP-1 was also found as a transcription factor that mediates gene induction by the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and hence the name TRE1 1The abbreviations used are: TRETPA (12-O-tetradecanoylphorbol-13-acetate) response elementMAPKmitogen-activated protein kinaseSREserum response elementTCFternary complex factorCBPCREB binding proteinJAKJanus kinaseERKextracellular stimulus responsive kinaseATFactivating transcription factorJNKJun N-terminal kinaseCREBcAMP response element binding proteinFRKFos regulating kinaseMEKMAPK or ERK kinase. 1The abbreviations used are: TRETPA (12-O-tetradecanoylphorbol-13-acetate) response elementMAPKmitogen-activated protein kinaseSREserum response elementTCFternary complex factorCBPCREB binding proteinJAKJanus kinaseERKextracellular stimulus responsive kinaseATFactivating transcription factorJNKJun N-terminal kinaseCREBcAMP response element binding proteinFRKFos regulating kinaseMEKMAPK or ERK kinase.(TPA response element) for its recognition site(4Angel P. Imagawa M. Chiu R. Stein B. Imbra R.J. Rahmsdorf H.J. Jonat C. Herrlich P. Karin M. Cell. 1987; 49: 729-739Abstract Full Text PDF PubMed Scopus (2152) Google Scholar). Following its discovery, AP-1 activity was found to be induced by many other stimuli, including growth factors, cytokines, T cell activators, neurotransmitters, and UV irradiation (1Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3256) Google Scholar). Several mechanisms are involved in induction of AP-1 activity and may be classified as those that increase the abundance of AP-1 components and those that stimulate their activity. A complete discussion of all the mechanisms that regulate AP-1 activity, either positively or negatively, is beyond the scope of this minireview, and the reader is referred to an earlier, more comprehensive review(1Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3256) Google Scholar). The present review focuses on the role of mitogen-activated protein kinases (MAPKs) in regulation of AP-1 activity. The regulation and functions of these important signal-transducing enzymes were recently reviewed(5Marshall C.J. Cell. 1995; 80: 179-185Abstract Full Text PDF PubMed Scopus (4225) Google Scholar, 6Cobb M. Goldsmith E.J. J. Biol. Chem. 1995; 270: 14843-14846Abstract Full Text Full Text PDF PubMed Scopus (1659) Google Scholar). TPA (12-O-tetradecanoylphorbol-13-acetate) response element mitogen-activated protein kinase serum response element ternary complex factor CREB binding protein Janus kinase extracellular stimulus responsive kinase activating transcription factor Jun N-terminal kinase cAMP response element binding protein Fos regulating kinase MAPK or ERK kinase. TPA (12-O-tetradecanoylphorbol-13-acetate) response element mitogen-activated protein kinase serum response element ternary complex factor CREB binding protein Janus kinase extracellular stimulus responsive kinase activating transcription factor Jun N-terminal kinase cAMP response element binding protein Fos regulating kinase MAPK or ERK kinase. The reader should be aware that although AP-1 DNA binding activity can be conveniently measured by electrophoretic mobility shift or footprinting assays, changes in AP-1 DNA binding activity do not mirror the transcriptional activity of this complex factor. Therefore, when dealing with AP-1, it is critical to measure its ability to activate transcription of an AP-1-dependent reporter gene. A useful promoter for such experiments is that of the human collagenase gene (4Angel P. Imagawa M. Chiu R. Stein B. Imbra R.J. Rahmsdorf H.J. Jonat C. Herrlich P. Karin M. Cell. 1987; 49: 729-739Abstract Full Text PDF PubMed Scopus (2152) Google Scholar). The reasons for this discrepancy are several. First and foremost, several proteins can form complexes that bind to AP-1 sites. These proteins, however, differ considerably in their ability to activate transcription of target genes. For instance, both c-Fos and Fra-1 form stable heterodimers with any of the Jun proteins, and these heterodimers have similar DNA binding activities and specificities, yet c-Fos has a potent transactivation domain that is absent from the smaller Fra-1 protein(7Suzuki T. Okuno H. Yoshida T. Endo T. Nishina H. Iba H. Nucleic Acids Res. 1992; 19: 5537-5542Crossref Scopus (194) Google Scholar). Second, phosphorylation at specific sites enhances the transactivating potential of several AP-1 proteins, including c-Jun and c-Fos, without having any effect on their DNA binding activities(8Smeal T. Binetruy B. Mercola D. Grover-Bardwick A. Heidecker G. Rapp U.R. Karin M. Mol. Cell. Biol. 1992; 12: 3507-3513Crossref PubMed Scopus (305) Google Scholar, 9Deng T. Karin M. Nature. 1994; 371: 171-175Crossref PubMed Scopus (318) Google Scholar). Most of the genes that encode AP-1 components behave as “immediate-early” genes, i.e. genes whose transcription is rapidly induced, independently of de novo protein synthesis, following cell stimulation. Among these, the regulation of c-fos and c-jun transcription is best understood. Several cis elements mediate c-fos induction in response to a diverse spectrum of extracellular stimuli (reviewed in Ref. 10Treisman R. Trends Biochem. Sci. 1992; 17: 423-426Abstract Full Text PDF PubMed Scopus (349) Google Scholar). A cAMP response element mediates c-fos induction in response to neurotransmitters and polypeptide hormones which, by using either cAMP or Ca2+ as second messengers, activated either protein kinase A or calmodulin-dependent protein kinases, respectively(11Sheng M.E. Thompson M.A. Greenberg M.E. Science. 1994; 252: 1427-1430Crossref Scopus (1279) Google Scholar). A serum response element (SRE) mediates c-fos induction by growth factors, cytokines, and other stimuli that activate MAPKs(10Treisman R. Trends Biochem. Sci. 1992; 17: 423-426Abstract Full Text PDF PubMed Scopus (349) Google Scholar), and a Sis-inducible enhancer mediates induction by stimuli that activate the JAK group of protein kinases (12Darnell Jr., J.E. Kerr I.M. Stark G.R. Science. 1994; 264: 1415-1421Crossref PubMed Scopus (4974) Google Scholar). Given this complexity, it is not surprising that c-fos transcription is rapidly induced in response to almost any imaginable extracellular stimulus (Fig. 1A). The SRE is recognized by the serum response factor, whose binding results in recruitment of the ternary complex factor (TCF), which cannot bind to the SRE by itself(10Treisman R. Trends Biochem. Sci. 1992; 17: 423-426Abstract Full Text PDF PubMed Scopus (349) Google Scholar). Following mitogenic stimulation, Elk-1, one of several candidate TCFs(13Treisman R. Curr. Opin. Genet. & Dev. 1994; 4: 96-101Crossref PubMed Scopus (619) Google Scholar), is rapidly phosphorylated, most likely by members of the ERK group of MAPKs(14Gille H. Sharrocks A. Shaw P. Nature. 1992; 358: 414-417Crossref PubMed Scopus (814) Google Scholar, 15Marais R. Wynne J. Treisman R. Cell. 1993; 73: 381-393Abstract Full Text PDF PubMed Scopus (1104) Google Scholar). Phosphorylation of Elk-1 was reported to facilitate formation of the ternary complex composed of itself, the serum response factor, and the SRE (14Gille H. Sharrocks A. Shaw P. Nature. 1992; 358: 414-417Crossref PubMed Scopus (814) Google Scholar) and to stimulate its ability to activate transcription, without affecting its DNA binding properties(15Marais R. Wynne J. Treisman R. Cell. 1993; 73: 381-393Abstract Full Text PDF PubMed Scopus (1104) Google Scholar). Since in vivo the SRE appears to be constitutively occupied(10Treisman R. Trends Biochem. Sci. 1992; 17: 423-426Abstract Full Text PDF PubMed Scopus (349) Google Scholar), increased Elk-1 transcriptional activity is a more likely mechanism by which ERK activation causes c-fos induction. The sites at which Elk-1 is phosphorylated are clustered within its C-terminal activation domain and are conserved in other candidate TCFs, such as SAP-1(13Treisman R. Curr. Opin. Genet. & Dev. 1994; 4: 96-101Crossref PubMed Scopus (619) Google Scholar). Since the SRE also mediates c-fos induction in response to stimuli such as UV irradiation(16Buscher M. Rahmsdorf H.J. Liftin M. Karin M. Herrlich P. Oncogene. 1988; 3: 301-311PubMed Google Scholar), which has only a marginal effect on ERK activity(17Minden A. Lin A. Smeal T. Dérijard B. Cobb M. Davis R. Karin M. Mol. Cell. Biol. 1994; 14: 6683-6688Crossref PubMed Scopus (436) Google Scholar), it is possible that Elk-1 or other TCFs are also phosphorylated by other MAPKs (see below). Nevertheless, ERK activation leads to elevated AP-1 activity via c-fos induction. This results in increased synthesis of c-Fos, which upon translocation to the nucleus combines with pre-existing Jun proteins to form AP-1 dimers that are more stable than those formed by Jun proteins alone(18Smeal T. Angel P. Meek J. Karin M. Genes & Dev. 1989; 3: 2091-2100Crossref PubMed Scopus (185) Google Scholar). Increased stability results in higher levels of AP-1 DNA binding activity because it shifts the equilibrium toward dimer formation, which is essential for DNA binding. By comparison with c-fos, the c-jun promoter is somewhat simpler, and most of its inducers operate through one major cis element, the c-jun TRE (Fig. 1B). This TRE differs from the consensus TRE sequence by 1-base pair insertion(19Angel P. Hattori K. Smeal T. Karin M. Cell. 1988; 55: 875-885Abstract Full Text PDF PubMed Scopus (990) Google Scholar), and due to this subtle change it is more efficiently recognized by c-Jun·ATF2 heterodimers than by conventional AP-1 complexes(20van Dam H. Duyndam M. Rottier R. Bosch A. de Vries-Smits L. Herrlich P. Zantema A. Angel P. van der Eb A.J. EMBO J. 1993; 12: 479-487Crossref PubMed Scopus (342) Google Scholar). Unlike c-Jun, ATF2 is a constitutively expressed protein. However, despite its inducible expression, most cell types contain some c-Jun protein prior to their stimulation. Like the c-fos SRE, the c-jun TRE is constitutively occupied in vivo(21Rozek D. Pfeifer G.P. Mol. Cell. Biol. 1993; 13: 5490-5499Crossref PubMed Scopus (115) Google Scholar). Following exposure to stimuli that activate members of the JNK group of MAPKs(22Dérijard B. Hibi M. Wu I.-H. Barrett T. Su B. Deng T. Karin M. Davis R.J. Cell. 1994; 76: 1-20Abstract Full Text PDF PubMed Scopus (2953) Google Scholar), both c-Jun (23Devary Y. Gottlieb R. Smeal T. Bauskin A.R. Ben-Neriah Y. Karin M. Cell. 1992; 71: 1081-1091Abstract Full Text PDF PubMed Scopus (795) Google Scholar) and ATF2 (24Gupta S. Campbell D. Derijard B. Davis R.J. Science. 1995; 267: 389-393Crossref PubMed Scopus (1336) Google Scholar) are rapidly phosphorylated. The constitutive occupancy of the c-jun TRE indicates that this phosphorylation occurs while the proteins are bound to the c-jun promoter. Similarly, in the case of c-fos, Elk-1 must be phosphorylated while bound to DNA. Phosphorylation of c-Jun and ATF2 stimulates their ability to activate transcription, thereby leading to c-jun induction. Thus, part of the increase in AP-1 activity in response to JNK-activating stimuli (such as tumor necrosis factor α, UV irradiation) is due to increased c-Jun synthesis and possibly c-Fos synthesis (as the JNKs may also phosphorylate and activate Elk-1; see below). Another part of the increase in AP-1 activity is due to c-Jun phosphorylation. The activities of both pre-existing and newly synthesized AP-1 components are modulated through their phosphorylation. So far, this form of posttranslational control was demonstrated for c-Jun, c-Fos, and ATF2, but it is likely that other Jun and Fos proteins are similarly regulated. In the case of c-Jun, phosphorylation at a cluster of sites located next to its basic region inhibits DNA binding by c-Jun homodimers but not by c-Jun·c-Fos heterodimers(25Boyle W.J. Smeal T. Defize L.H.K. Angel P. Woodgett J.R. Karin M. Hunter T. Cell. 1991; 64: 573-584Abstract Full Text PDF PubMed Scopus (852) Google Scholar). On the other hand, phosphorylation of c-Jun at Ser-73 and Ser-63, located within its transactivation domain, potentiates its ability to activate transcription as either a homodimer (26Pulverer B.J. Kyriakis J.M. Avruch J. Nikolakaki E. Woodgett J.R. Nature. 1991; 353: 670-674Crossref PubMed Scopus (1191) Google Scholar, 27Smeal T. Binetruy B. Mercola D.A. Birrer M. Karin M. Nature. 1991; 354: 494-496Crossref PubMed Scopus (697) Google Scholar) or a heterodimer with c-Fos(9Deng T. Karin M. Nature. 1994; 371: 171-175Crossref PubMed Scopus (318) Google Scholar). These residues, which do not affect DNA binding activities, are phosphorylated by the newly discovered members of the MAPK family, the Jun kinases or JNKs(22Dérijard B. Hibi M. Wu I.-H. Barrett T. Su B. Deng T. Karin M. Davis R.J. Cell. 1994; 76: 1-20Abstract Full Text PDF PubMed Scopus (2953) Google Scholar, 28Hibi M. Lin A. Smeal T. Minden A. Karin M. Genes & Dev. 1993; 7: 2135-2148Crossref PubMed Scopus (1708) Google Scholar). So far, the JNKs are the only protein kinases found to efficiently phosphorylate the N-terminal sites of c-Jun. Interestingly, neither ERK1 nor ERK2 phosphorylates the N-terminal stimulatory sites of c-Jun and instead phosphorylate one of the inhibitory sites located next to the C-terminal DNA binding domain (17Minden A. Lin A. Smeal T. Dérijard B. Cobb M. Davis R. Karin M. Mol. Cell. Biol. 1994; 14: 6683-6688Crossref PubMed Scopus (436) Google Scholar, 29Chou S. Baichval V. Ferrell Jr., J.E. Mol. Biol. Cell. 1992; 3: 1117-1180Crossref PubMed Scopus (59) Google Scholar). Using an altered specificity mutant of c-Jun that is phosphorylated by protein kinase A instead of JNK, phosphorylation of Ser-73 (and Ser-63 to a lesser extent) was demonstrated to be directly responsible for potentiating the transactivation function(30Smeal T. Hibi M. Karin M. EMBO J. 1994; 13: 6006-6010Crossref PubMed Scopus (84) Google Scholar). Phosphorylation may potentiate c-Jun transcriptional activity through recruitment of CREB binding protein (CBP), a protein that was originally identified by virtue of its binding to phospho-CREB, another bZIP transcription factor that is activated by protein kinase A(31Arias J. Alberts A.S. Brindle P. Claret F.X. Smeal T. Karin M. Feramisco J. Montminy M. Nature. 1994; 370: 226-229Crossref PubMed Scopus (680) Google Scholar, 32Kwok R.P. Lundblad J.R. Chrivia J.C. Richards J.P. Bachinger H.P. Brennan R.G. Roberts S.G. Green M.R. Goodman R.H. Nature. 1994; 370: 223-226Crossref PubMed Scopus (1280) Google Scholar). Following phosphorylation of its N-terminal sites, but not the C-terminal sites, c-Jun can bind CBP and CBP can potentiate its ability to activate transcription(31Arias J. Alberts A.S. Brindle P. Claret F.X. Smeal T. Karin M. Feramisco J. Montminy M. Nature. 1994; 370: 226-229Crossref PubMed Scopus (680) Google Scholar). CBP is postulated to connect the phosphorylated activation domains of CREB or c-Jun to the basal transcriptional machinery. Interestingly, the sequence surrounding the N-terminal phosphoacceptors of c-Jun is also conserved in the C-terminal activation domain of c-Fos (33Sutherland J.A. Cook A. Bannister A.J. Kouzarides T. Genes & Dev. 1992; 6: 1810-1819Crossref PubMed Scopus (99) Google Scholar), suggesting that phosphorylation at Thr-232, the homolog of Ser-73 of c-Jun, potentiates c-Fos transcriptional activity. This prediction had turned out to be correct. However, despite the similarity between the two phosphoacceptor sites, Thr-232 of c-Fos is not phosphorylated by either JNK1 or JNK2 but by a novel 88-kDa MAPK termed FRK(9Deng T. Karin M. Nature. 1994; 371: 171-175Crossref PubMed Scopus (318) Google Scholar). Like the ERKs and the JNKs, FRK is a proline-directed kinase, whose activity is rapidly stimulated in response to Ha-Ras activation by growth factors. Although the mechanism by which phosphorylation at Thr-232 stimulates c-Fos transcriptional activity is not clear, in the context of a c-Jun·c-Fos heterodimer, phosphorylation of each protein makes a similar contribution to stimulation of transcriptional activity, suggesting that both activation domains interact with the transcriptional machinery. A similar situation may apply for c-Jun·ATF2 heterodimers, as ATF2 phosphorylation at Thr-63 and Thr-71 within its N-terminal activation domain was recently shown to stimulate its transcriptional activity (22Dérijard B. Hibi M. Wu I.-H. Barrett T. Su B. Deng T. Karin M. Davis R.J. Cell. 1994; 76: 1-20Abstract Full Text PDF PubMed Scopus (2953) Google Scholar). Like c-Jun, ATF2 is also phosphorylated by the JNKs(24Gupta S. Campbell D. Derijard B. Davis R.J. Science. 1995; 267: 389-393Crossref PubMed Scopus (1336) Google Scholar). Transactivation by ATF2 is also potentiated upon binding of Rb or E1A, probably through recruitment of additional activation domains to the DNA-bound ATF2 dimer(34Kim S.J. Wagner S. Liu F. O'Reilly M.A. Robbins P.D. Green M.R. Nature. 1992; 358: 331-334Crossref PubMed Scopus (212) Google Scholar). Both E1A and Rb act in concert with phosphorylation of ATF2(24Gupta S. Campbell D. Derijard B. Davis R.J. Science. 1995; 267: 389-393Crossref PubMed Scopus (1336) Google Scholar). Although E1A can induce c-jun transcription(20van Dam H. Duyndam M. Rottier R. Bosch A. de Vries-Smits L. Herrlich P. Zantema A. Angel P. van der Eb A.J. EMBO J. 1993; 12: 479-487Crossref PubMed Scopus (342) Google Scholar), it represses AP-1 activity(35Offringa R. Gebel S. van Dam H. Timmers M. Smits A. Zwart R. Stein B. Bos J.L. van der Eb A. Herrlich P. Cell. 1990; 62: 527-538Abstract Full Text PDF PubMed Scopus (99) Google Scholar). This repression could be mediated through competition for CBP, which is very similar to the p300 E1A binding protein(36Arany F. Sellers W.R. Livingstone D.M. Eickner R. Cell. 1994; 97: 799-800Abstract Full Text PDF Scopus (370) Google Scholar). Indeed, it was recently shown that p300 and CBP are functionally interchangeable and that E1A can inhibit the coactivation function of both factors(37Arany Z. Newsome D. Oldread E. Livingston D.M. Eckner R. Nature. 1995; 374: 81-84Crossref PubMed Scopus (490) Google Scholar, 38Lundblad J.R. Kwok R.P.S. Laurance M.E. Harter M.L. Goodman R.H. Nature. 1995; 374: 85-88Crossref PubMed Scopus (531) Google Scholar). As described above, three different types of MAPKs, the ERKs, the JNKs, and FRKs, contribute to induction of AP-1 activity in response to a diverse array of extracellular stimuli. It is of considerable interest that each of these types of MAPKs is affecting AP-1 activity through phosphorylation of a different substrate (Fig. 2). While the ERKs phosphorylate TCF/Elk-1 and thereby induce c-Fos synthesis, they do not phosphorylate c-Jun or c-Fos on sites that potentiate their transcriptional activities(9Deng T. Karin M. Nature. 1994; 371: 171-175Crossref PubMed Scopus (318) Google Scholar, 17Minden A. Lin A. Smeal T. Dérijard B. Cobb M. Davis R. Karin M. Mol. Cell. Biol. 1994; 14: 6683-6688Crossref PubMed Scopus (436) Google Scholar, 29Chou S. Baichval V. Ferrell Jr., J.E. Mol. Biol. Cell. 1992; 3: 1117-1180Crossref PubMed Scopus (59) Google Scholar). In addition, the ERKs do not appear to be involved in ATF2 phosphorylation (24Gupta S. Campbell D. Derijard B. Davis R.J. Science. 1995; 267: 389-393Crossref PubMed Scopus (1336) Google Scholar). The JNKs, on the other hand, phosphorylate the stimulatory sites of c-Jun and ATF2 but do not phosphorylate c-Fos(9Deng T. Karin M. Nature. 1994; 371: 171-175Crossref PubMed Scopus (318) Google Scholar, 24Gupta S. Campbell D. Derijard B. Davis R.J. Science. 1995; 267: 389-393Crossref PubMed Scopus (1336) Google Scholar, 28Hibi M. Lin A. Smeal T. Minden A. Karin M. Genes & Dev. 1993; 7: 2135-2148Crossref PubMed Scopus (1708) Google Scholar). The JNKs are also capable of phosphorylation and activation of TCF/Elk-1, suggesting they may be involved in c-fos induction under certain circumstances.2 2M. Cavigelli and M. Karin, far, is only to affect c-Fos T. Karin M. Nature. 1994; 371: 171-175Crossref PubMed Scopus (318) Google Scholar). These results that MAPKs are specific in their of and do not phosphorylate any or that is by a as The mechanisms this of substrate specificity are with the as a phosphorylation by the JNKs a located between and of M. Lin A. Smeal T. Minden A. Karin M. Genes & Dev. 1993; 7: 2135-2148Crossref PubMed Scopus (1708) Google Scholar, V. S. Sci. S. A. 1992; PubMed Scopus Google Scholar). In this mediates binding of c-Jun to the JNKs, and although complexes have not yet in the of the is essential for phosphorylation and stimulation of c-Jun M. Lin A. Smeal T. Minden A. Karin M. Genes & Dev. 1993; 7: 2135-2148Crossref PubMed Scopus (1708) Google Scholar). The is not the only of c-Jun that phosphorylation by the JNKs, because in also to the JNKs through a similar region but is not phosphorylated by T. and M. Karin, is not phosphorylated by the JNKs because its of Ser-63 and Ser-73 of c-Jun are not by are these in the Deng and M. Karin, In to the and at the phosphorylation of Jun proteins by the JNKs specific the phosphoacceptor These residues, however, are not a part of the and do not affect JNK the binding of the two human JNKs to c-Jun was JNK2 was found to bind than T. Su B. Dérijard B. G. Davis R. Karin M. Genes & Dev. 1994; PubMed Scopus Google Scholar). the of JNK2 toward c-Jun is than the of JNK1 toward c-Jun and its is T. Su B. Dérijard B. G. Davis R. Karin M. Genes & Dev. 1994; PubMed Scopus Google Scholar). The of JNK2 measured with other are not considerably different from those of and JNK1 may be the more kinase for other The for the higher of JNK2 toward c-Jun was to a region of located its T. Su B. Dérijard B. G. Davis R. Karin M. Genes & Dev. 1994; PubMed Scopus Google Scholar). This which is all MAPKs, is not a part of the Most it is the element of JNK2 that with the sites on c-Jun, as in In to the in substrate specificities, the three types of MAPKs that affect AP-1 activity differ in their to extracellular stimuli. The ERKs are most efficiently stimulated by growth and phorbol M. Goldsmith E.J. J. Biol. Chem. 1995; 270: 14843-14846Abstract Full Text Full Text PDF PubMed Scopus (1659) Google Scholar, 17Minden A. Lin A. Smeal T. Dérijard B. Cobb M. Davis R. Karin M. Mol. Cell. Biol. 1994; 14: 6683-6688Crossref PubMed Scopus (436) Google Scholar, J.M. P. Nikolakaki E. T. Avruch J. Woodgett J.R. Nature. 1994; PubMed Scopus Google Scholar), FRK to growth but not to phorbol T. Karin M. Nature. 1994; 371: 171-175Crossref PubMed Scopus (318) Google Scholar). FRK nor ERK activities are considerably stimulated by exposure to UV irradiation or tumor necrosis factor, stimuli that are for JNK activation T. Karin M. Nature. 1994; 371: 171-175Crossref PubMed Scopus (318) Google Scholar, 17Minden A. Lin A. Smeal T. Dérijard B. Cobb M. Davis R. Karin M. Mol. Cell. Biol. 1994; 14: 6683-6688Crossref PubMed Scopus (436) Google Scholar, H. Sharrocks A. Shaw P. Nature. 1992; 358: 414-417Crossref PubMed Scopus (814) Google Scholar). with the and the ERKs, JNK activity is stimulated by growth A. Lin A. Smeal T. Dérijard B. Cobb M. Davis R. Karin M. Mol. Cell. Biol. 1994; 14: 6683-6688Crossref PubMed Scopus (436) Google Scholar, 38Lundblad J.R. Kwok R.P.S. Laurance M.E. Harter M.L. Goodman R.H. Nature. 1995; 374: 85-88Crossref PubMed Scopus (531) Google Scholar, J.M. P. Nikolakaki E. T. Avruch J. Woodgett J.R. Nature. 1994; PubMed Scopus Google Scholar). The in JNK activity are UV irradiation (22Dérijard B. Hibi M. Wu I.-H. Barrett T. Su B. Deng T. Karin M. Davis R.J. Cell. 1994; 76: 1-20Abstract Full Text PDF PubMed Scopus (2953) Google Scholar, 28Hibi M. Lin A. Smeal T. Minden A. Karin M. Genes & Dev. 1993; 7: 2135-2148Crossref PubMed Scopus (1708) Google Scholar) or activation of T T. Su B. Dérijard B. G. Davis R. Karin M. Genes & Dev. 1994; PubMed Scopus Google Scholar). Although all three types of kinases are stimulated in response to P. Hattori K. Smeal T. Karin M. Cell. 1988; 55: 875-885Abstract Full Text PDF PubMed Scopus (990) Google Scholar, A. Lin A. M. C. Derijard B. Davis R.J. Karin M. Science. 1994; Scopus Google Scholar, M. E. Cobb Sci. S. A. 1992; PubMed Scopus Google Scholar, M. G. S. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar), the JNKs also to A. Lin A. M. C. Derijard B. Davis R.J. Karin M. Science. 1994; Scopus Google Scholar). However, activation ERK and JNK through different kinase (Fig. The major leading from to ERK is on the recruitment of to the S.J. C.J. Nature. 1994; PubMed Scopus Google Scholar). This results in activation of a kinase that phosphorylates and the specificity kinases and P. W. T. L. Roberts T. T. Science. 1992; Scopus Google Scholar). The are responsible for phosphorylation and activation of the A. Science. 1992; PubMed Scopus Google Scholar). also a kinase in its to C. A. K. G. Science. 1993; PubMed Scopus Google Scholar, Science. 1994; PubMed Scopus Google Scholar). So far, between and has and it is not it is activated by Although in is an C. A. K. G. Science. 1993; PubMed Scopus Google Scholar, Science. 1994; PubMed Scopus Google Scholar), in vivo it or a specificity kinase that phosphorylates and the A. Lin A. M. C. Derijard B. Davis R.J. Karin M. Science. 1994; Scopus Google Scholar, B.J. K. Woodgett J.R. J. J.M. Nature. 1994; PubMed Scopus Google Scholar, B. J. Barrett T. Wu J. R.J. Davis R.J. Science. 1995; 267: PubMed Scopus Google Scholar, A. Minden A. H. Claret F.X. C. F. Karin M. Science. 1995; PubMed Scopus Google Scholar). In the it be of interest to the that contribute to the specificity of and it to the JNK activation on the other hand, has only a marginal effect on activity, and of the can activate the JNKs A. Lin A. M. C. Derijard B. Davis R.J. Karin M. Science. 1994; Scopus Google Scholar, A. Minden A. H. Claret F.X. C. F. Karin M. Science. 1995; PubMed Scopus Google Scholar). not activate the B. J. Barrett T. Wu J. R.J. Davis R.J. Science. 1995; 267: PubMed Scopus Google Scholar, A. Minden A. H. Claret F.X. C. F. Karin M. Science. 1995; PubMed Scopus Google Scholar). Thus, the kinase responsible for ERK and JNK activation are and very (Fig. While a to be the mechanisms that contribute to the regulation of AP-1 activity and most of the important target genes whose is modulated by the different of AP-1 are yet to be a has by on this transcription factor and its response to extracellular stimuli. Most the of AP-1 regulation had some of the mechanisms by which protein phosphorylation transcription factor activity (reviewed in Ref. T. Karin M. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar) and the used by cell to with the nucleus (reviewed in Ref. Treisman R. Cell. 1995; 80: Full Text PDF PubMed Scopus Google Scholar). In to the of important AP-1 target genes that the functions of the different of this transcription factor, a major for the is the mechanisms that specificity to the of protein kinases and transcription factors. It is that and proteins the components of AP-1 and the MAPK can be involved in specific P. for of the and T. and B. Su for of the