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Meeting Highlights

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Selected Symposia Related to Signaling in Disease at CSN 2011

30 January 2012

Nancy R. Gough

Joan Massagué (Memorial Sloan-Kettering Cancer Center, New York, NY) kicked off the scientific meeting by discussing his lab’s work on the role of transforming growth factor β (TGF-β) in stem cells and cancer. He argues that in embryonic stem cells, certain master regulators of cell fate are “poised” for response to TGF-β stimulation, but not fully inaccessible. This is in contrast to “homeostatic” genes, which are fully accessible. TGF-β signaling is mediated through activation of transcriptional regulators of the Smad family. Most Smads interact with the common Smad, Smad4, but TRIM33 is an alternative to Smad4 in some protein complexes containing Smad2 or Smad3 (Smad2/3), leading to complex combinatorial gene regulation profiles. Some genes require both TRIM33-Smad2/3 and Smad4-Smad2/3 complexes for activation, whereas others and require only one or the other. The master regulatory genes require both complexes.

In addition to Smads, TRIM33 also binds acetylated and methylated histones at “poised” genes. Separate TRIM33-Smad2/3 and Smad4-Smad2/3 complexes bind to the promoters of master regulator genes, and it appears that the TRIM33-Smad2/3 complex promotes binding of the Smad4-Smad2/3 complex. Thus, TRIM33 and Smad4 appear to coordinately activate master regulators of cell fate. This may relate to cancer in that TGF-β may act as a tumor suppressor by promoting differentiation and thus eliminating “stemness.” In some cancers, the cancer cells exhibit corruption of the pathway through which TGF-β promotes differentiation to act as a tumor supporessor and instead allows TGF-β signaling to promote cell survival and metastasis. Therefore, it would be better to target the genes that enable the cells to be stimulated by TGF-β, rather than TGF-β itself.

Related Reading
Q. Xi, Z. Wang, A. I. Zaromytidou, X. H. Zhang, L. F. Chow-Tsang, J. X. Liu, H. Kim, A. Barlas, K. Manova-Todorova, V. Kaartinen, L. Studer, W. Mark, D. J. Patel, J. Massagué, A poised chromatin platform for TGF-β access to master regulators. Cell 147, 1511-1524 (2011). [PubMed]

T. Oskarsson, S. Acharyya, X. H. Zhang, S. Vanharanta, S. F. Tavazoie, P. G. Morris, R. J. Downey, K. Manova-Todorova, E. Brogi, J. Massagué, Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med. 17, 867-874 (2011). [PubMed]

J. Massagué, TGFβ in cancer. Cell 134, 215-230 (2008). [PubMed]

W. He, D. C. Dorn, H. Erdjument-Bromage, P. Tempst, M. A. Moore, J. Massagué, Hematopoiesis controlled by distinct TIF1γ and Smad4 branches of the TGFβ pathway. Cell 125, 929-941 (2006). [PubMed]

Related Resources in Science Signaling
L. Mishra, K. Kitisin, T. Saha, T. Blake, N. Golestaneh, M. Deng, C. Kim, Y. Tang, K. Shetty, B. Mishra, TGF-β signaling in development. Sci. Signal. (Connections Map in the Database of Cell Signaling, as seen 20 January 2012). [Canonical Pathway]

A. Atfi, R. Baron, p53 brings a new twist to the Smad signaling network. Sci. Signal. 1, pe33 (2008). [Abstract] [Full Text]


Gokhan Hotamisligil (Harvard School of Public Health, Boston, MA) talked about obesity, which he called “the 21st century’s chronic disease plague,” emphasizing the relationship between inflammation and obesity. He calls the kind of inflammatory response associated with obesity “metainflammation”, because it is associated with the general condition of reduced metabolic activity, rather than localized swelling, redness, and heat associated with classical inflammation.

Obesity is associated with increased (tumor necrosis factor-α) TNF-α production by fat cells and stromal cells. When the gene encoding TNF-α is knocked out, mice exhibit improved glucose tolerance; and when inflammatory signaling is inhibited in human patients, there is also improved glucose handling. Insulin receptor signaling is inhibited by (i) classic inflammatory mediators, like TNF-α and IL-1, (evolutionarily this may be because an infected animal needs to redirect nutrients and metabolic processes to fighting infection, not cell growth and other processes responsive to insulin), (ii) nutrients, which stimulate inflammatory signaling and the inflammasome directly, and (iii) internal stress as indicated by the endoplasmic reticulum (ER) stress response, also called the unfolded protein response (UPR).

UPR is activated in obese animals, especially in the liver. UPR is connected to inflammatory signaling through the kinases JNK and IKK. Limited clinical trials suggest that alleviation of UPR may be helpful in treating diabetes. Analysis of protein abundance in livers from lean and obese mice suggests that the ER chaperone adaptive response may be defective, because there are more components of lipid synthesis machinery and autophagic degradation machinery in the obese animal livers without a concomitant increase in ER chaperones.

Analysis of the abundance of the lipids in lean and obese mouse livers showed that the ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) was higher in the obese animals. This altered lipid composition could affect the activities of integral membrane proteins, like calcium channels and the ER-localized calcium pump SERCA. When the PC/PE ratio is too high, SERCA is inhibited in vitro and in vivo. Treatments that reduce the PC/PE ratio or induce expression of an alternate isoform of SERCA (SERCA2b) result in improved glucose tolerance, reduced UPR, and better calcium handling in the liver ER.

Related Reading
L. P. Bechmann, R. A. Hannivoort, G. Gerken, G. S. Hotamisligil, M. Trauner, A. Canbay, The interaction of hepatic lipid and glucose metabolism in liver diseases. J. Hepatol. Epub ahead of print 13 Dec 2011. [PubMed]

S. Fu, L. Yang, P. Li, O. Hofmann, L. Dicker, W. Hide, X. Lin, S. M. Watkins, A. R. Ivanov, G. S. Hotamisligil, Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473, 528-531 (2011). [PubMed]

F. Engin, G. S. Hotamisligil, Restoring endoplasmic reticulum function by chemical chaperones: An emerging therapeutic approach for metabolic diseases. Diabetes Obes Metab. Suppl 2, 108-115 (2010). [PubMed]

G. S. Hotamisligil, Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140, 900-917 (2010). [PubMed]

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Y. Qiu, T. Mao, Y. Zhang, M. Shao, J. You, Q. Ding, Y. Chen, D. Wu, D. Xie, X. Lin, X. Gao, R. J. Kaufman, W. Li, Y. Liu, A Crucial Role for RACK1 in the Regulation of Glucose-Stimulated IRE1 Activation in Pancreatic β Cells. Sci. Signal. 3, ra7 (2010). [Abstract] [Full Text]

D. L. Eizirik, M. Cnop, ER Stress in Pancreatic β Cells: The Thin Red Line Between Adaptation and Failure. Sci. Signal. 3, pe7 (2010). [Abstract] [Full Text]

V. Mieulet, L. Yan, C. Choisy, K. Sully, J. Procter, A. Kouroumalis, S. Krywawych, M. Pende, S. C. Ley, C. Moinard, R. F. Lamb, TPL-2–mediated activation of MAPK downstream of TLR4 signaling is coupled to arginine availability. Sci. Signal. 3, ra61 (2010). [Abstract] [Full Text]


M. Angela Nieto (Instituto de Neurociencias, San Juan de Alicante, Spain) presented an overview of the role of the transcription factor Snail in epithelial-to-mesenchymal transition (EMT) and how Snail may contribute to cancer. Snail controls EMT during development and becomes reactivated in invasive cells in tumors (both in mouse models and in human cancers), where it represses E-cadherin expression. EMT is "reversible" in the embryo – some cells can undergo EMT, migrate to their destinations, then undergo MET (mesechymal-to-epithelial transition), and this phenotype switching can happen multiple times. EMT is also important for wound healing and tissue regeneration.

Snail has been implicated in renal failure and fibrotic kidney disease. Human patients with renal fibrosis have very high amounts of Snail in the kidney. Removing Snail specifically in the kidneys markedly reduced kidney inflammation and fibrosis in a mouse model of obstructive ureter disease. Snail activation in the adult kidney is associated with altered cellular morphology, induction of markers of mesenchyme and of renal fibrosis, and can lead to renal failure. If fibrosis is triggered by Snail induction in mice and then Snail induction is stopped, the fibrosis in the kidney is reduced and organ function improves. Thus, Snail is involved in both cancer invasivenes and diseases associated with tissue fibrosis.

Related Reading
M. A. Nieto, Epithelial-Mesenchymal Transitions in development and disease: old views and new perspectives. Int J Dev. Biol. 53, 1541-1547 (2009). [PubMed]

A. Boutet, M. A. Esteban, P. H. Maxwell, M. A. Nieto, Reactivation of Snail genes in renal fibrosis and carcinomas: a process of reversed embryogenesis? Cell Cycle. 6, 638-642 (2007). [PubMed]

Boutet A, De Frutos CA, Maxwell PH, Mayol MJ, Romero J, Nieto MA, Snail activation disrupts tissue homeostasis and induces fibrosis in the adult kidney. EMBO J. 25, 5603-5613 (2006). [PubMed]

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D. Iliopoulos, C. Polytarchou, M. Hatziapostolou, F. Kottakis, I. G. Maroulakou, K. Struhl, P. N. Tsichlis, MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells. Sci. Signal. 2, ra62 (2009). [Abstract] [Full Text]

S. Stinson, M. R. Lackner, A. T. Adai, N. Yu, H.-J. Kim, C. O’Brien, J. Spoerke, S. Jhunjhunwala, Z. Boyd, T. Januario, R. J. Newman, P. Yue, R. Bourgon, Z. Modrusan, H. M. Stern, S. Warming, F. J. de Sauvage, L. Amler, R.-F. Yeh, D. Dornan, TRPS1 Targeting by miR-221/222 Promotes the Epithelial-to-Mesenchymal Transition in Breast Cancer. Sci. Signal. 4, ra41 (2011). [Abstract] [Full Text]

A. Ruiz i Altaba, Hedgehog signaling and the Gli code in stem cells, cancer, and metastases. Sci. Signal. 4, pt9 (2011). [Abstract] [Full Text] [Slideshow]

S. Stinson, M. R. Lackner, A. T. Adai, N. Yu, H.-J. Kim, C. O’Brien, J. Spoerke, S. Jhunjhunwala, Z. Boyd, T. Januario, R. J. Newman, P. Yue, R. Bourgon, Z. Modrusan, H. M. Stern, S. Warming, F. J. de Sauvage, L. Amler, R.-F. Yeh, D. Dornan, miR-221/222 targeting of Trichorhinophalangeal 1 (TRPS1) promotes epithelial-to-mesenchymal transition in breast cancer. Sci. Signal. 4, pt5 (2011). [Abstract] [Full Text] [Slideshow]

Y.-G. Yoo, J. Christensen, J. Gu, L. E. Huang, HIF-1α mediates tumor hypoxia to confer a perpetual mesenchymal phenotype for malignant progression. Sci. Signal. 4, pt4 (2011). [Abstract] [Full Text] [Slideshow]


J. Silvio Gutkind (National Institute of Dental and Craniofacial Research, Bethesda, MD) described his lab’s work on targeting virally-encoded G protein-coupled receptors (GPCRs) or chemokine receptor signaling as a means to target cancer. GPCRs and G proteins can be oncogenes, and . vViruses, such as Kaposi's sSarcoma-associated hHerpesvirus (KSHV), encode active vGPCRs. KPSV is a common tumor-inducing virus in immune-compromised patients. The KSHV vGPCR activates the target of rapamycin (TOR) pathway through phosphoinositide 3-kinase γ (PI3Kγ), and blocking this pathway with rapamycin reduced tumor growth.

Chemokine receptors are GPCRs and can be used by cancer cells to mediate migration. The receptor CXCR4 is a GPCR that promotes migration toward a source of its chemokine ligand, SDF-1. In cancer cells, the promigratory signal may occur through atypical G protein coupling - that is, these receptors may couple to a different G protein than the one they typically use in noncancerous or other cells. His lab used G protein receptors activated solely by artificial ligands (Gi RASSL) to identify a pathway from CXCR4 to the Rho kinase ROCK through Gα12/13, which promoted migration of cancer cells. Based on studies with xenografted tumors in mice, disruption of this pathway may be effective at preventing metastasis. Some of this work was published in the 20 September 2011 issue of Science Signaling.

Related Reading
D. Martin, R. Galisteo, A. A. Molinolo, R. Wetzker, E. Hirsch, J. S. Gutkind, PI3Kγ mediates kaposi's sarcoma-associated herpesvirus vGPCR-induced sarcomagenesis. Cancer Cell 19, 805-813 (2011). [PubMed]

A. Sodhi, R. Chaisuparat, J. Hu, A. K. Ramsdell, B. D. Manning, E. A. Sausville, E. T. Sawai, A. Molinolo, J. S. Gutkind, S. Montaner, The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. Cancer Cell 10, 133-143 (2006). [PubMed]

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J. S. Gutkind, A. M. VanHook, Science Signaling podcast: 20 September 2011. Sci. Signal. 4, pc19 (2011). [Abstract] [Podcast]

E. Slinger, D. Maussang, A. Schreiber, M. Siderius, A. Rahbar, A. Fraile-Ramos, S. A. Lira, C. Söderberg-Nauclér, M. J. Smit, HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the IL-6–STAT3 axis. Sci. Signal. 3, ra58 (2010). [Abstract] [Full Text]

C. T. Veldkamp, C. Seibert, F. C. Peterson, N. B. De la Cruz, J. C. Haugner, III, H. Basnet, T. P. Sakmar, B. F. Volkman, Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12. Sci. Signal. 1, ra4 (2008). [Abstract] [Full Text]


Richard Flavell (Yale University School of Medicine) described an elegant genetic dissection of the role of the innate immune signaling pathway mediated by inflammosomes in regulation of the intestinal microflora. Nod-like receptors (NLRs) constitute an intracellular arm of the innate immune system that detects the consequences of pathogen infection or cellular damage. The Nod family includes NOD (nucleotide-binding oligomerization domain), IPAF (ICE protease activating factor), and NLRP (Nod-like receptor protein) and in mammals there are more than 35 genes encoding members of this family. Nod proteins have a leucine-rich repeat (LRR), a nucleotide-binding domain, and a protein interaction domain (either a pyrin domain or a caspase recruitment domain) and, through the formation of the inflammasome, they activate caspase 1, which in turn activates the proinflammatory mediators interleukin-1β (IL-1β) and IL-18. For example, NLRP3 is an NLR with a pyrin domain that recognizes viral and bacterial pathogens, Plasmodium, and fungi, as well as environmental toxins (silica, asbestos, the vaccine adjuvant alum) and endogenous mediators (ATP, uric acid, b-amyloid, cholesterol crystals, DNA, and RNA).

After this introduction to the inflammasome and the NLRs, he discussed his lab’s investigation into the role of NLRP6 and the inflammasome in the regulation of the response to intestinal microbes. The intestinal microflora are essential for metabolism, nutrient absorption, and production of vitamins. They found that mice deficient in NLRP6 or the inflammasome response exhibited an altered intestinal flora that could be spread to wild-type mice housed in the same cage. This altered intestinal flora made the mice more susceptible to chemically induced colitis.

Using an elegant genetic analysis, he defined a pathway in the colonic epithelium from NLRP6 to the inflammasome to caspase 1 to IL-18, which was important for regulating the bacterial composition of the intestine. When wild-type mice were housed with mice in which this pathway was compromised, the wild-type mice became more susceptible to chemically induced colitis. The inflammasome-compromised mice transmitted “contagious” colitis to their wild-type cage mates (remember that mice are coprophagic). The bacteria responsible for the transmissible colitis were determined through sequence analysis.

Related Reading
E. Elinav, T. Strowig, J. Henao-Mejia, R. A. Flavell, Regulation of the antimicrobial response by NLR proteins. Immunity 34, 665-679 (2011). [PubMed]

E. Elinav, T. Strowig, A. L. Kau, J. Henao-Mejia, C. A. Thaiss, C. J. Booth, D. R. Peaper, J. Bertin, S. C. Eisenbarth, J. I. Gordon, R. A. Flavell, NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745-757 (2011). [PubMed]

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E. M. Adler, Allies from within. Sci. Signal. 1, ec204 (2008). [Abstract]

K. L. Mueller, A gut feeling. Sci. Signal. 3, ec194 (2010) [Abstract]

W.-J. Lee, Bacterial-modulated signaling pathways in gut homeostasis. Sci. Signal. 1, pe24 (2008). [Abstract] [Full Text]

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