LAP (NF-IL6 or C/EBP beta), is a liver transcriptional activator protein that confers liver-specific gene expression. Because LAP has a characteristic phosphoacceptor sequence for cAMP-dependent protein kinase A (PKA), we tested if in vitro phosphorylation of LAP by PKA modulates its interaction with specific DNA sequences. The major PKA phosphorylation site of LAP was identified as Ser105, which is a predicted PKA site. As expected, this PKA phosphorylation site disappears after mutation of Ser105 to Ala. Kinetic studies with LAP and LAP Asp105 (which mimics a phosphoserine residue) demonstrated that phosphorylation of Ser105 itself has no effect on DNA binding. Phosphorylation of other sites by PKA, identified in the region between Ser173 and Ser223 and at Ser240, by analysis of truncated and mutated LAP peptides, resulted in an inhibition of DNA binding. LAP was also phosphorylated by purified protein kinase C in vitro, and the major phosphoacceptor was shown to be Ser240 within the DNA-binding domain of LAP. Phosphorylation of LAP at this residue or introduction of a Ser240 to Asp mutation resulted in marked decrease in its binding to DNA. These results suggest that site-specific phosphorylations of LAP modulate transactivation of its target genes.
Sedentary (sitting) time is a newly identified risk factor for obesity and chronic diseases, which is behaviorally and physiologically distinct from lack of physical activity. To inform public health approaches to influencing sedentary behaviors, an understanding of correlates is required.Participants were 2,199 adults aged 20-66 years living in King County/Seattle, WA, and Baltimore, MD, regions, recruited from neighborhoods high or low on a "walkability index" (derived from objective built environment indicators) and having high or low median incomes. Cross-sectional associations of walkability and income with total sedentary time (measured by accelerometers and by self-report) and with self-reported time in seven specific sitting-related behaviors were examined.Neighborhood walkability and income were unrelated to measures of total sitting time. Lower neighborhood walkability was significantly associated with more driving time (difference of 18.2 min/day, p < .001) and more self-reported TV viewing (difference of 14.5 min/day, p < .001). Residents of higher income neighborhoods reported more computer/Internet and reading time, and they had more objectively measured sedentary time.Neighborhood walkability was not related to total sedentary time but was related to two specific sedentary behaviors associated with risk for obesity-driving time and TV viewing time. Future research could examine how these prevalent and often prolonged sedentary behaviors mediate relationships between neighborhood walkability and overweight/obesity. Initiatives to reduce chronic disease risk among residents of both higher-and lower-income low-walkable neighborhoods should include a focus on reducing TV viewing time and other sedentary behaviors and enacting policies that can lead to the development or redevelopment of more-walkable neighborhoods. (PsycINFO Database Record (c) 2012 APA, all rights reserved).
Abstract Colorectal cancer (CRC) is the third leading cause of cancer related deaths in the US and other Western countries. Whereas 2% of CRC arises in the context of pre-existing inflammatory bowel disease (IBD), especially ulcerative colitis (UC), and is known as colitis associated cancer (CAC), most CRC, including familial and sporadic cases, is found in individuals that do not show any signs of IBD. Yet, expression profiling has revealed the same inflammatory gene signature, which depends on activation of NF-κB and STAT3, in both CAC and CRC, findings that generate a question regarding the origin of the CRC-elicited inflammatory response. In early experiments we have shown that activation of NF-κB, which leads to production of the pro-inflammatory cytokine IL-6, a potent activator of STAT3, plays a critical role in the development of CAC. More recently we investigated the origin and role of inflammation in the development and progression of sporadic CRC, most of which is driven by loss of the tumor suppressor APC and activation of the β catenin signaling pathway. We focused our studies on IL-23, a heterodimeric cytokine, composed of a unique p19 subunit and a p40 subunit which it shares with IL-12. As observed by others, we also found that IL-23 expression is strongly elevated in CRC relative to adjacent non-tumor tissue and have extended these findings to the CPC-APC mouse model of colorectal tumorigenesis. In CPC-APC mice, the major source of IL-23 expression in colorectal adenomas are tumor associated macrophages (TAM). Importantly, ablation of IL-23 p19 either in all cells or only in bone marrow (BM)-derived cells attenuates the development and slows down the progression of CRC in CPC-APC mice and similar results were observed upon ablation of IL-23 receptor (IL-23R). As IL-23R is not expressed on adenoma epithelial cells, IL-23 must exert its pro-tumorigenic effect via an indirect mechanism. Indeed, IL-23 signaling promotes the polarization of IL-17 producing T cells (Th17) and the production of IL-6, both of which contribute to the development and progression of sporadic colorectal tumors in mice. Importantly, molecular epidemiological studies carried out by Galon, Fridman and their co-workers have revealed that an “IL-23-Th17” signature that is upregulated in about 10% of human CRC patients, and that the presence of this signature in stage I/II CRC is associated with very poor prognosis and a marked decrease in disease free survival. We investigated the mechanism responsible for the specific induction of IL-23 in TAM and found it to depend on Toll like receptor (TLR) - MyD88 signaling, which appears to be activated in response to components of the colonic microflora that permeate the adenomas. We also detected eubacterial 16S RNA in both mouse and human colonic adenomas, as well as increased penetrance of bacterial endotoxin (LPS) into adenomas relative to surrounding non-cancerous tissue. The development of colorectal adenomas in both mice and men is associated with loss of protective mucins and junctional adhesion proteins and this is likely to be the primary mechanism that accounts for the selective entry of microbial products into the tumor and induction of the tumor promoting “IL-23-Th17” signature. Future studies should focus on the therapeutic value of anti-IL-23 or anti-IL-17 interventions and the genetic or environmental causes of the large variation in the magnitude of IL-17 production amongst human CRC patients. References 1. Greten, F.R., Eckmann, L., Greten, T.F., Park, J.M., Li, Z-W, Egan, L.J., Kagnoff, M.F. and Karin, M. (2004) IKKβ links inflammation and tumorigenesis in a mouse model of colitis associated cancer. Cell 118:285-296. 2. Grivennikov, S., Karin, E., Terzic, J., Mucida, D., Yu, G.Y., Vallabhapurapu, S., Scheller, J., Rose-John, S., Cheroutre, H., Eckmann, L., Karin, M. (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15:103-13. 3. Terzic, J., Grivennikov, S., Karin, E., Karin, M. (2010) Inflammation and Colon Cancer. Gastroenterology 138: 2101-2114.e5 4. Grivennikov, S., Greten, F., Karin, M. (2010) Immunity, Inflammation and Cancer. Cell 140:883-899. 5. Grivennikov, S., Wang, K., Mucida, D., Stewart, C-A., Schnabl, B., Jauch, D., Taniguchi, K., Yu, G., Österreicher, C.H., Hung, K.E., Datz, C., Feng, Y., Fearon, E.R., Oukka, M., Tessarollo, L., Coppola, V., Yarovinsky, F., Cheroutre, H., Eckmann, L., Trinchieri, G., Karin, M. (2012) Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature in press. Citation Format: Michael Karin. Tumor elicited inflammation and malignant progression in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY40-01. doi:10.1158/1538-7445.AM2014-SY40-01
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Journal Article Familial Similarities of Changes in Cognitive, Behavioral, and Physiological Variables in a Cardiovascular Health Promotion Program Get access Thomas L. Patterson, Thomas L. Patterson 2 University of CaliforniaSan Diego 2All correspondence should be sent to Thomas L. Patterson, Division of General Pediatrics Child and Family Health Studies, M-031F, University of California, San Diego, La Jolla, California 92093-0631. Search for other works by this author on: Oxford Academic PubMed Google Scholar James F. Sallis, James F. Sallis University of CaliforniaSan Diego Search for other works by this author on: Oxford Academic PubMed Google Scholar Philip R. Nader, Philip R. Nader University of CaliforniaSan Diego Search for other works by this author on: Oxford Academic PubMed Google Scholar Robert M. Kaplan, Robert M. Kaplan University of CaliforniaSan Diego Search for other works by this author on: Oxford Academic PubMed Google Scholar Joan W. Rupp, Joan W. Rupp University of CaliforniaSan Diego Search for other works by this author on: Oxford Academic PubMed Google Scholar Catherine J. Atkins, Catherine J. Atkins San Diego State University Search for other works by this author on: Oxford Academic PubMed Google Scholar Karen L. Senn Karen L. Senn San Diego State University Search for other works by this author on: Oxford Academic PubMed Google Scholar Journal of Pediatric Psychology, Volume 14, Issue 2, June 1989, Pages 277–292, https://doi.org/10.1093/jpepsy/14.2.277 Published: 01 June 1989 Article history Received: 22 September 1988 Accepted: 20 December 1988 Published: 01 June 1989
