A major goal of cancer research is the identification of tumor-specific vulnerabilities that can be exploited for the development of therapies that are selectively toxic to the tumor. We show here that the transcriptional coactivators peroxisome proliferatoractivated receptor gamma coactivator 1␤ (PGC1␤) and estrogen-related receptor ␣ (ERR␣) are aberrantly expressed in human colon cell lines and tumors. With kinase suppressor of Ras 1 (KSR1) depletion as a reference standard, we used functional signature ontology (FUSION) analysis to identify the ␥1 subunit of AMP-activated protein kinase (AMPK) as an essential contributor to PGC1␤ expression and colon tumor cell survival. Subsequent analysis revealed that a subunit composition of AMPK (␣2␤2␥1) is preferred for colorectal cancer cell survival, at least in part, by stabilizing the tumor-specific expression of PGC1␤. In contrast, PGC1␤ and ERR␣ are not detectable in nontransformed human colon epithelial cells, and depletion of the AMPK␥1 subunit has no effect on their viability. These data indicate that Ras oncogenesis relies on the aberrant activation of a PGC1␤-dependent transcriptional pathway via a specific AMPK isoform.A third of all human cancers, including a substantial percentage of colorectal, lung, and pancreatic cancers, are driven by activating mutations in Ras genes. Activating K-Ras mutations are present in 35 to 40% of colon tumors and are thought to be both drivers of tumorigenesis and determinants of therapeutic regimens (1). Therapeutic disruption of Ras function has been clinically ineffective to date, but investigation of Ras pleiotropy continues to yield a diversity of downstream effectors with obligate roles in the maintenance and adaptation of Ras-driven tumors to changing environments. The Raf-MEK-extracellular signal-regulated kinase (ERK) signaling pathway is essential for the oncogenic properties of mutated K-Ras (2). However, numerous potent and specific MEK inhibitors have been developed yet have failed to demonstrate single-agent efficacy in cancer treatment (3). As a molecular scaffold of the Raf-MEK-ERK kinase cascade (4, 5), kinase suppressor of Ras 1 (KSR1) is necessary and sufficient for Ras V12 -induced tumorigenesis (4), mouse embryo fibroblast (MEF) transformation (5, 6), and pancreatic cancer growth (7) but dispensable for normal development (4). KSR1 is overexpressed in endometrial carcinoma and is required for both proliferation and anchorage-independent growth of endometrial cancer cells (8). Except for minor defects in hair follicles, KSR1 knockout mice are fertile and develop normally (4).This observation predicts that small molecules targeting KSR1 and functionally related effectors should preferentially target Rasdriven tumors while leaving normal tissue largely unaffected. More generally, this observation demonstrates that tumor cells, while under selective pressure to adapt to inhospitable environments and proliferate without constraint, will adopt strategies that, while advantageous to that singular purpose, create...

Interleukin-2 is a multifaceted cytokine with both immunostimulatory and immunosuppressive properties. Our laboratory recently demonstrated that the availability of IL-2 is regulated, in part, by association with perlecan, a heparan sulfate proteoglycan. Given the abundance of perlecan in blood vessels, we asked whether IL-2 is present in vessel walls. Our results indicate that IL-2 is associated with endothelial and smooth muscle cells within the human arterial wall. This IL-2 is released by heparanase, and promotes the proliferation of an IL-2 dependent cell line. Given the presence of IL-2 in human arteries, we asked whether the large vessels of IL-2 deficient mice were normal. The aortas of IL-2 deficient mice exhibited a loss of smooth muscle cells, suggesting that IL-2 may contribute to their survival. In their entirety, these results suggest a here-to-fore unrecognized role of IL-2 in vascular biology, and have significant implications for both the immune and cardiovascular systems.

ObjectiveKinase Suppressor of Ras 2 (KSR2) is a molecular scaffold coordinating Raf/MEK/ERK signaling that is expressed at high levels in the brain. KSR2 disruption in humans and mice causes obesity and insulin resistance. Understanding the anatomical location and mechanism of KSR2 function should lead to a better understanding of physiological regulation over energy balance.MethodsMice bearing floxed alleles of KSR2 (KSR2fl/fl) were crossed with mice expressing the Cre recombinase expressed by the Nestin promoter (Nes-Cre) to produce Nes-CreKSR2fl/fl mice. Growth, body composition, food consumption, cold tolerance, insulin and free fatty acid levels, glucose, and AICAR tolerance were measured in gender and age matched KSR2−/− miceResultsNes-CreKSR2fl/fl mice lack detectable levels of KSR2 in the brain. The growth and onset of obesity of Nes-CreKSR2fl/fl mice parallel those observed in KSR2−/− mice. As in KSR2−/− mice, Nes-CreKSR2fl/fl are glucose intolerant with elevated fasting and cold intolerance. Male Nes-CreKSR2fl/fl mice are hyperphagic, but female Nes-CreKSR2fl/fl mice are not. Unlike KSR2−/− mice, Nes-CreKSR2fl/fl mice respond normally to leptin and AICAR, which may explain why the degree of obesity of adult Nes-CreKSR2fl/fl mice is not as severe as that observed in KSR2−/− animals.ConclusionsThese observations suggest that, in the brain, KSR2 regulates energy balance via control of feeding behavior and adaptive thermogenesis, while a second KSR2-dependent mechanism, functioning through one or more other tissues, modulates sensitivity to leptin and activators of the energy sensor AMPK.

Zinc (Zn) is required for proper immune function and host defense. Zn homeostasis is tightly regulated by Zn transporters that coordinate biological processes through Zn mobilization. Zn deficiency is associated with increased susceptibility to bacterial infections, including Streptococcus pneumoniae, the most commonly identified cause of community-acquired pneumonia. Myeloid cells, including macrophages and dendritic cells (DCs), are at the front line of host defense against invading bacterial pathogens in the lung and play a critical role early on in shaping the immune response. Expression of the Zn transporter ZIP8 is rapidly induced following bacterial infection and regulates myeloid cell function in a Zn-dependent manner. To what extent ZIP8 is instrumental in myeloid cell function requires further study. Using a novel, myeloid-specific, Zip8 knockout model, we identified vital roles of ZIP8 in macrophage and DC function upon pneumococcal infection. Administration of S. pneumoniae into the lung resulted in increased inflammation, morbidity, and mortality in Zip8 knockout mice compared with wild-type counterparts. This was associated with increased numbers of myeloid cells, cytokine production, and cell death. In vitro analysis of macrophage and DC function revealed deficits in phagocytosis and increased cytokine production upon bacterial stimulation that was, in part, due to increased NF-κB signaling. Strikingly, alteration of myeloid cell function resulted in an imbalance of Th17/Th2 responses, which is potentially detrimental to host defense. These results (for the first time, to our knowledge) reveal a vital ZIP8- and Zn-mediated axis that alters the lung myeloid cell landscape and the host response against pneumococcus.