The key visual G protein, transducin undergoes bi-directional translocations between the outer segment (OS) and inner compartments of rod photoreceptors in a light-dependent manner thereby contributing to adaptation and neuroprotection of rods. A mammalian uncoordinated 119 protein (UNC119), also known as Retina Gene 4 protein (RG4), has been recently implicated in transducin transport to the OS in the dark through its interaction with the N-acylated GTP-bound transducin-␣ subunit (G␣ t1 ). Here, we demonstrate that the interaction of human UNC119 (HRG4) with transducin is dependent on the N-acylation, but does not require the GTP-bound form of G␣ t1 . The lipid specificity of UNC119 is unique: UNC119 bound the myristoylated N terminus of G␣ t1 with much higher affinity than a prenylated substrate, whereas the homologous prenyl-binding protein PrBP/␦ did not interact with the myristoylated peptide. UNC119 was capable of interacting with G␣ t1 GDP as well as with heterotrimeric transducin (G t ). This interaction of UNC119 with G t led to displacement of G 1 ␥ 1 from the heterotrimer. Furthermore, UNC119 facilitated solubilization of G t from dark-adapted rod OS membranes. Consistent with these observations, UNC119 inhibited rhodopsin-dependent activation of G t , but had no effect on the GTP-hydrolysis by G␣ t1 . A model for the role of UNC119 in the IS3 OS translocation of G t is proposed based on the UNC119 ability to dissociate G t subunits from each other and the membrane. We also found that UNC119 inhibited activation of G o by D2 dopamine receptor in cultured cells. Thus, UNC119 may play conserved inhibitory role in regulation of GPCR-G protein signaling in non-visual tissues.In rod photoreceptors, exposure to bright light causes translocation of the visual G protein, transducin from the photosensitive outer segments (OS) 2 to the inner compartments of the cells (reviewed in Refs. 1-3). The light-dependent translocation of transducin is thought to play an important role in light-adaptation and neuroprotection (4, 5). Significant advances have been made in understanding the mechanism of this phenomenon. The current evidence supports a simple diffusion model, whereby the activation of transducin by photoexcited rhodopsin (R*) causes dissociation of transducin-␣ (G␣ t1 ) and G 1 ␥ 1 subunits allowing them to diffuse into the inner segment (1-9). However, translocated transducin must return to the OS during dark adaptation to restore rod sensitivity. This retrograde translocation occurs on a relatively slow time scale with a halflife of 2.5 h (4). The precise mechanism of transducin return to the OS in the dark is not known. Formation of heterotrimeric G t in the inner segment (IS) appears to be a prerequisite for correct transport of transducin to the OS. Heterotrimeric G t forms in the IS in the absence of R* following hydrolysis of G␣ t1 -bound GTP. GTP and GTP␥S both caused light-dependent transducin redistribution from the OS in permeabilized retinas, but only GTP-translocated G t returned to the OS i...
Although targeting lipogenesis for cancer treatment appears to have a strong rationale, drug discovery in this field has not been fully explored due to the lack of understanding the mode of action as well as the therapeutic window. We reported previously on a class of novel ACC inhibitors with potent and selective activity against human ACC1, an isoform overexpressed in many cancer types. These ACC inhibitors revealed strong anti-tumor activity, including induction of tumor cell apoptosis in vitro and tumor regression in vivo in a sub-set of tumor models. To further demonstrate the therapeutic potential of ACC inhibitors, we conducted a series of studies in xenograft mice and rat to evaluate the anti-tumor efficacy of ACC inhibitors and to characterize their safety profile. We report that breast, prostate, and pancreatic cancers are among the most sensitive tumors to ACC inhibition. Interestingly, the anti-tumor kinetics correlated with reduction in palmitate levels without substantial changes in structural lipid components. In addition, a sub-type of KRAS mutation and activation of the Wnt pathway correlates with the sensitivity of tumors to ACC inhibitors. Treatment with ACC inhibitors at high doses caused an immediate decrease in food intake and followed with body weight loss. A clear correlation between the reduction of food intake and exposure of ACC inhibitor was observed. Upon withdrawing drug, the effect on food intake is restored. Therefore, we investigated intermittent dosing schedules and food effects on the tolerability and anti-tumor efficacy of ACC inhibitors. We could demonstrate that the tolerability was improved without compromising the efficacy compared to continuous treatment. Furthermore, feeding animals a high fat diet prevented body weight loss and meanwhile maintained the antitumor activity. These results indicate that strong reduction of food intake seems the cause of intolerability, which can be prevented and reversed either by intermittent dosing, or by exogenously supplementing with a high fat diet. Furthermore, for the first time we provided in vivo evidence that exogenous lipids could complement de novo lipogenesis inhibition in normal cells, while tumor growth requires lipogenesis irrespective of existing circulating lipids. In summary, these assessments provide scientific insights and strategy on how to best target tumor lipid metabolism and lipid signaling effectively and safely for cancer therapy. Citation Format: Ningshu Liu, Wilhelm Bone, Sendhil S. Velan, Krishnarao Doddapuneni, Jadegoud Yaligar, Kai Thede Thede, Ursula Moenning, Xiaohe Shi, Xianfeng Tian, Elissaveta Petrova1, Franz von Nussbaum, Dominik Mumberg, Michael Brands, Karl Ziegelbauer. How to develop ACC1 inhibitors targeting lipid metabolism and oncogenic signaling pathways effectively and safely. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1129. doi:10.1158/1538-7445.AM2015-1129
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