The MAPK pathway is activated in the majority of melanomas and is the target of therapeutic approaches. Under normal conditions, it initiates the so-called immediate early response, which encompasses the transient transcription of several genes belonging to the AP-1 transcription factor family. Under pathological conditions, such as continuous MAPK pathway overactivation due to oncogenic alterations occurring in melanoma, these genes are constitutively expressed. The consequences of a permanent expression of these genes are largely unknown. Here, we show that FOSL1 is the main immediate early AP-1 member induced by melanoma oncogenes. We first examined its role in established melanoma cells. We found that FOSL1 is involved in melanoma cell migration as well as cell proliferation and anoikis-independent growth, which is mediated by the gene product of its target gene HMGA1, encoding a multipotent chromatin modifier. As FOSL1 expression is increased in patient melanoma samples compared to nevi, we investigated the effect of enhanced FOSL1 expression on melanocytes. Intriguingly, we found that FOSL1 acts oncogenic and transforms melanocytes, enabling subcutaneous tumor growth in vivo. During the process of transformation, FOSL1 reprogrammed the melanocytes and downregulated MITF in a HMGA1-dependent manner. At the same time, AXL was upregulated, leading to a shift in the MITF/AXL balance. Furthermore, FOSL1 re-enforced pro-tumorigenic transcription factors MYC, E2F3 and AP-1. Together, this led to the enhancement of several growth-promoting processes, such as ribosome biogenesis, cellular detachment and pyrimidine metabolism. Overall, we demonstrate that FOSL1 is a novel reprogramming factor for melanocytes with potent tumor transformation potential.

Members of the transient receptor potential (TRP) superfamily are broadly expressed in our body and contribute to multiple cellular functions. Most interestingly, the fourth member of the vanilloid family of TRP channels (TRPV4) serves different partially antagonistic functions in the respiratory system. This review highlights the role of TRPV4 channels in lung fibroblasts, the lung endothelium, as well as the alveolar and bronchial epithelium, during physiological and pathophysiological mechanisms. Data available from animal models and human tissues confirm the importance of this ion channel in cellular signal transduction complexes with Ca2+ ions as a second messenger. Moreover, TRPV4 is an excellent therapeutic target with numerous specific compounds regulating its activity in diseases, like asthma, lung fibrosis, edema, and infections.

Sustained exposure of the lung to various environmental or occupational toxins may eventually lead to pulmonary fibrosis, a devastating disease with no cure. Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix (ECM) proteins such as fibronectin and collagens. The peptidase plasmin degrades the ECM, but protein levels of the plasmin activator inhibitor-1 (PAI-1) are increased in fibrotic lung tissue, thereby dampening plasmin activity. Transforming growth factor-β1 (TGF-β1)-induced activation of SMAD transcription factors promotes ECM deposition by enhancing collagen, fibronectin and PAI-1 levels in pulmonary fibroblasts. Hence, counteracting TGF-β1-induced signaling is a promising approach for the therapy of pulmonary fibrosis. Transient receptor potential cation channel subfamily M Member 7 (TRPM7) supports TGF-β1-promoted SMAD signaling in T-lymphocytes and the progression of fibrosis in kidney and heart. Thus, we investigated possible effects of TRPM7 on plasmin activity, ECM levels and TGF-β1 signaling in primary human pulmonary fibroblasts (pHPF). We found that two structurally unrelated TRPM7 blockers enhanced plasmin activity and reduced fibronectin or PAI-1 protein levels in pHPF under basal conditions. Further, TRPM7 blockade strongly inhibited fibronectin and collagen deposition induced by sustained TGF-β1 stimulation. In line with these data, inhibition of TRPM7 activity diminished TGF-β1-triggered phosphorylation of SMAD-2, SMAD-3/4-dependent reporter activation and PAI-1 mRNA levels. Overall, we uncover TRPM7 as a novel supporter of TGF-β1 signaling in pHPF and propose TRPM7 blockers as new candidates to control excessive ECM levels under pathophysiological conditions conducive to pulmonary fibrosis.

Our respiratory system is exposed to toxicants and pathogens from both sides: the airways and the vasculature. While tracheal, bronchial and alveolar epithelial cells form a natural barrier in the airways, endothelial cells protect the lung from perfused toxic compounds, particulate matter and invading microorganism in the vascular system. Damages induce inflammation by our immune response and wound healing by (myo)fibroblast proliferation. Members of the transient receptor potential (TRP) superfamily of ion channel are expressed in many cells of the respiratory tract and serve multiple functions in physiology and pathophysiology. TRP expression patterns in non-neuronal cells with a focus on TRPA1, TRPC6, TRPM2, TRPM5, TRPM7, TRPV2, TRPV4 and TRPV6 channels are presented, and their roles in barrier function, immune regulation and phagocytosis are summarized. Moreover, TRP channels as future pharmacological targets in chronic obstructive pulmonary disease (COPD), asthma, cystic and pulmonary fibrosis as well as lung edema are discussed.

Stromal interaction molecules (STIM1, 2) are acting as sensors for Ca 2+ in intracellular stores and activate Orai channels at the plasma membrane for store-operated Ca 2+ entry (SOCE), while classical transient receptor potential (TRPC) channel mediate receptor-operated Ca 2+ entry (Roce). Several reports, however, indicate a role for TRPC in SOCE in certain cell types. Here, we analyzed Ca 2+ influx and cell function in TRPC1/6-deficient (TRPC1/6 −/− ) and STIM1/2-deficient (STIM1/2 ΔpmLf ) primary murine lung fibroblasts (pmLF). As expected, SOCE was decreased in STIM1/2-deficient pmLF and ROCE was decreased in TRPC1/6 −/− pmLF compared to control cells. By contrast, SOCE was not significantly different in TRPC1/6 −/− pmLF and ROCE was similar in STIM1/2-deficient pmLF compared to Wt cells. Most interestingly, cell proliferation, migration and nuclear localization of nuclear factor of activated T-cells (NFATc1 and c3) were decreased after ablation of STIM1/2 proteins in pmLF. In conclusion, TRPC1/6 channels are not involved in SOCE and STIM1/2 deficiency resulted in decreased cell proliferation and migration in pmLf.Store-operated Ca 2+ entry (SOCE) also named capacitive Ca 2+ entry (CCE) was first described by J.W. Putney Jr. more than 30 years ago as depletion of intracellular Ca 2+ stores which induces the opening of plasma membrane (PM) Ca 2+ channels 1 . Since then, candidate proteins like classical transient receptor potential (TRPC) channels 2 and mechanisms, e.g. coupling of TRPC proteins to inositol 1-4-5 trisphosphate (IP3) receptor channels in the endoplasmic reticulum 3,4 for SOCE, were intensively discussed in the scientific community. In 2005 however, stromal interaction molecules (Stim in Drosophila and STIM1, STIM2 in humans) were identified as Ca 2+ sensors in the ER directly regulating SOCE in two different large-scale screening approaches 5,6 . One year later, Ca 2+ selective channels at the plasma membrane (Orai) were discovered 7-9 , which were responsible for Ca 2+ release activated Ca 2+ (CRAC) currents originally described in mast cells 10 . A molecular model was developed to support the concept that upon ER Ca 2+ depletion STIM proteins homo-multimerize and translocate to ER-PM junctions 11,12 , where they recruit and gate Orai channels via direct interaction 13 . Ca 2+ influx through Orai channels is important for cellular remodeling, e.g. in cardiovascular diseases 14 , and mutations in these channels are responsible for multiple channelopathies 15 . Irrespective of these events, TRP channels trigger Ca 2+ influx in response to extracellular stimuli or receptor activation (receptor-operated Ca 2+ influx, ROCE) independently of STIM and Orai 16 . Some labs, however, reported that TRPC channels also interact with STIM proteins 17 and/or Orai channels 18 . Along these lines, TRPC channels like TRPC1 were invoked in SOCE in certain cells of salivary glands 19 and pancreatic acini 20 , while in vascular smooth muscle cells TRPC1 channels work independently of SOCE 21 . The role of TRPC1 i...