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Background: The increase in atmospheric CO 2 is causing a number of changes in plant growth such as increases in leaf area and number, branching, plant size and biomass, and growth rate. Despite the importance of stomatal responses to CO 2 , little is known about the genetic and molecular mechanisms that mediate stomatal development and movement in response to CO 2 levels. Deciphering the mechanisms that sense changes in CO 2 and/or HCO 3 − concentration is critical for unraveling the role of CO 2 in stomatal development movement. In Arabidopsis, CO 2-induced stomatal closure is strongly Ca 2+-dependent. To further dissect this signaling pathway and identify new components in the CO 2 response pathway, we recorded [Ca 2+ ] cyt changes in mutagenized Arabidopsis leaves and screened for mutants with abnormal guard cell behavior in response to CO 2 /HCO 3 −. Results: We observed that 1 mM HCO 3 − induces [Ca 2+ ] cys transient changes in guard cells and stomatal closure both in light and darkness. The changes in [Ca 2+ ] cys induced by HCO 3 − could be detected by an aequorin-based calcium imaging system. Using this system, we identified a number of Arabidopsis mutants defective in both [Ca 2+ ] cyt changes and the stomatal response to CO 2 /HCO 3 −. Conclusions: We provide a sensitive method for isolating stomatal CO 2 /HCO 3 − response genes that function early in stomatal closure and that have a role in regulating [Ca 2+ ] cyt. This method will be helpful in elucidating the Ca 2+-dependent regulation of guard cell behavior in response to CO 2 /HCO 3 − .

The last five years have seen a rapid increase in interest and understanding of signal transduction pathways. While the description of such pathways has become more detailed and complex, a number of consistent findings have emerged. Modular domains, such as SH2 and SH3 domains, are present on a wide variety of proteins and mediate specific protein-protein interactions. By defining the interaction mediated by such domains, a 'language' of interaction between proteins in signalling pathways is emerging. As more signalling proteins are identified it has become apparent that most oncogenes and tumour suppressor genes are components of major signalling pathways. Therefore, studies on the basic biology of signal transduction are having a direct impact on our understanding of cell transformation. With the characterisation of signalling pathways in a range of organisms, it has also become obvious that signalling pathways are ancient and have been highly conserved over the last billion years of evolution. A practical result of this finding has been the ability to exploit results obtained in genetically tractable invertebrate species such as C. elegans and Drosophila melanogaster to investigate signal transduction in mammals. This is an approach we have emphasized in our investigation of signal transduction by tyrosine kinase receptors in human and mouse cells. Results obtained in these studies with the Sos and Siah proteins are reviewed.

Lung cancer is the leading cause of cancer deaths worldwide. To advance the understanding of this disease, various genetically engineered and chemical induced mouse models have been established. However, most animal models resemble human lung adenocarcinoma, and spontaneous lung squamous cell carcinomas (SCCs) mouse models are very rare. Here, we generated Ikkα-KA/KA knock-in mice (KA/KA) in which an ATP binding site of IKKα, Lys 44 was replaced by alanine. The knock-in mice develop severe skin lesions and begin to die after 6 months. We found lung SCCs in some of the mice. To study lung SCC development, we decided to stabilize the skin condition by reintroducing transgenic IKKα by crossing KA/KA with Lori.IKKα transgenic mice to generate KA/KA/Lori.IKKα (KA/KAL) mice. Almost all the KA/KAL (100%) mice at 4 to 6 months of age developed spontaneous lethal lung SCCs. The endogenous IKKα protein level generally markedly declined in an age dependent manner in these IKKα mutant mice. Progenitor cell related markers Sox2, OCT3/4 and Nanog were only increased in the lung SCC tissue but not in the tumor adjacent tissues, implying the involvement of cancer stem cells in lung SCC. Furthermore, we detected substantial increases in Ras and CyclinD1 levels and EGFR, ERK and p38 activities in lung SCCs. On the other hand, we detected reduction in tumor suppressor gene Rb and IαBβ accompanying with reduced IKKα levels in KA/KAL lungs as well as in lung SCCs. Importantly, we observed a similar alteration pattern in mouse and human lung SCCs. Finally, reintroducing IKKα into lung epithelial cells prevented lung SCC development in mice. Collectively, our study supports the tumor suppressing role of IKKα in lung tumorigenesis. This novel lung SCC mouse model may facilitate investigations in pathogenesis, diagnosis, and treatment of human lung SCC disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2560. doi:1538-7445.AM2012-2560

Bacteria and fungi, two major components of the microbiota, generally share niches and develop both antagonistic and symbiotic relationships, regulating the pathological impacts on the host. The epithelium is where the bacterial-fungal interaction occurs most abundantly, but the relationship between the epithelium, bacteria, and fungi on the pathogenesis of numerous diseases, particularly tumorigenesis, is poorly understood. IKKα is one of the crucial factors regulating the homeostasis of squamous epithelial tissues. Recently, our lab has established a mouse model that develops esophageal squamous cell carcinomas (SCCs) associated with IKKα reduction, inflammation and chronic fungal infection. Cladosporium cladosporioides was a major type of fungi identified in this mouse model. Because IKKα deletion in the keratinocytes causes impaired skin barrier, we hypothesized that loss of epithelial IKKα may control fungal colonization through regulating the barrier integrity and inflammation, resulting in tumor promotion. We thus generated IKKαf/f mice with inducible K15.Cre (IKKαf/f/K15.Cre) which is expressed in skin stem cells, which are important for the epidermal formation and hair follicle development. After ablating IKKα in K15 cells in the oral mucosa and skin, IKKαf/f/K15.Cre mice were orally inoculated with Cladosporium cladosporioides. Loss of epithelial IKKα showed disruption of skin barrier functions and bacterial colonization in the oral mucosa and skin, oral dysplasia and skin SCC development. Interestingly, oral infection with Cladosporium further promoted bacterial colonization as well as skin tumorigenesis in IKKαf/f/K15.Cre mice. This suggests that epithelial IKKα loss can provoke oral bacterial-fungal symbiosis which contributes to tumor promotion. To confirm this hypothesis, we treated Cladosporium-infected IKKαf/f/K15.Cre mice with amoxicillin, an antibiotic, through drinking water. Amoxicillin treatment remarkably reduced skin tumor incidence in fungal-infected IKKαf/f/K15.Cre mice, indicating that oral bacterial-fungal symbiosis indeed promotes skin SCC development driven by epithelial IKKα reduction. We also detected bacterial colonization in human skin SCC tissue array as well as IKKα mutation in 17% of human skin SCC patients from the Cancer Genome Atlas database, supporting that the crosstalk between epithelial IKKα and bacterial-fungal symbiosis in skin SCC promotion is relavent to human diseases. Taken together, our data demonstrate that loss of epithelial IKKα induces the bacterial-fungal symbiosis in oral mucosa, promoting skin tumors. This study will shed light on the importance of the epithelial-bacterial-fungal interaction in the pathogenesis, proposing epithelial IKKα as a novel regulator of the bacterial-fungal interaction. Citation Format: Na-Young Song, Jami Willette-Brown, Feng Zhu, Yinling Hu. Crosstalk between epithelial-IKKα-deletion and symbiotic bacterial-fungal infection in skin carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5008.

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