ATXN1 Protein Family and CIC Regulate Extracellular Matrix Remodeling and Lung Alveolarization

Lee, Yoontae; Fryer, John Denis; Kang, Hyojin; Crespo-Barreto, Juan; Bowman, Aaron B.; Gao, Yan; Kahle, Juliette J.; Hong, Joon Seok; Kheradmand, Farrah; Orr, Harry T.; Finegold, Milton J.; Zoghbi, Huda Y.

doi:10.1016/j.devcel.2011.08.017

Cited by 93 publications

(157 citation statements)

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“…DEVELOPMENT 3966 a mouse model of spinocerebellar ataxia (Fryer et al, 2011) and in experiments with cultured mammalian cells (Dissanayake et al, 2011). We demonstrate that Cic lifetime is reduced in response to Torso RTK signaling in the Drosophila embryo.…”

Section: Discussionmentioning

confidence: 99%

“…Studies with cultured human cells and in a mouse model of spinocerebellar ataxia demonstrated that RTKs also counteract gene repression by Cic in vertebrates (Dissanayake et al, 2011;Fryer et al, 2011), but the mechanisms responsible for this effect are still poorly understood. Here, we investigate the RTK-dependent control of Cic in the early Drosophila embryo, the system where Cic was originally identified (Jiménez et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…In vertebrates, Cic is expressed in the developing cerebellum and controls matrix metalloproteases in the developing lung (Lee et al, 2002;Lee et al, 2011). Cic has been implicated in human diseases, including several cancers (Kawamura-Saito et al, 2006;Lam et al, 2006;Lim et al, 2008;Bettegowda et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Torso RTK controls Capicua degradation by changing its subcellular localization

et al. 2012

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SUMMARYThe transcriptional repressor Capicua (Cic) controls multiple aspects of Drosophila embryogenesis and has been implicated in vertebrate development and human diseases. Receptor tyrosine kinases (RTKs) can antagonize Cic-dependent gene repression, but the mechanisms responsible for this effect are not fully understood. Based on genetic and imaging studies in the early Drosophila embryo, we found that Torso RTK signaling can increase the rate of Cic degradation by changing its subcellular localization. We propose that Cic is degraded predominantly in the cytoplasm and show that Torso reduces the stability of Cic by controlling the rates of its nucleocytoplasmic transport. This model accounts for the experimentally observed spatiotemporal dynamics of Cic in the early embryo and might explain RTK-dependent control of Cic in other developmental contexts. DEVELOPMENTprotein Dronpa (Ando et al., 2004) or the fluorescent protein Venus (Nagai et al., 2002) and controlled by the regulatory sequences of the cic gene (Fig. 1A). The spatial distributions of Cic resulting from either of these constructs mimic the distribution of endogenous Cic (supplementary material Fig. S1).Cic is first detected after the 9th nuclear division . At this stage, Cic predominantly localizes to nuclei and levels in the middle region of the embryo are already significantly higher than those at the poles. Levels of Cic in the central region drop during mitoses, reflecting protein dispersal into the cytoplasm. During the subsequent interphase, nuclear levels recover and eventually exceed those observed in the preceding mitosis. The levels within individual nuclei increase ~2.5-fold between cycles 10 and the beginning of cycle 14. By contrast, levels at the poles remain low from the first time Cic is detected and until the embryo reaches the cellularization stage. Torso increases the rate of Cic degradationStudies in mice suggest that Cic-target gene derepression depends on RTK-dependent reduction of Cic levels (Fryer et al., 2011). To explore this mechanism in the embryo, we examined the degradation rates of Cic at different levels of RTK signaling. Based on the pattern of double-phosphorylated ERK (dpERK), which serves as a reporter of Torso signaling, the central region and poles of the wild-type embryo correspond to zero and maximal levels of Torso activation, respectively. To generate an intermediate level of Torso activation, we used a gain-of-function allele of torso (Szabad et al., 1989) (Fig. 2A,B).If Torso reduces the stability of Cic, its lifetime should be inversely correlated with the level of ERK activation. To test this prediction, we measured the lifetime of Cic using an optical pulselabeling method, which relies on the photo-switchable fluorescent protein Dronpa. Dronpa is synthesized in a bright state, which can be reversibly converted to the dark state by brief illumination at 3963 RESEARCH REPORT RTK-dependent control of Capicua 496 nm. The dark state is optically stable, but it can be converted back to the bright state ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Torso RTK controls Capicua degradation by changing its subcellular localization

et al. 2012

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“…In addition to these functions, in lung cancer, HOTAIR has been identified as a scaffold to facilitate the binding of E3 ubiquitinylases and corresponding substrates Ataxin-1 and Snurportin ( Figure 1C) (68). Ataxin-1 is essential for lung alveolization and therefore, HOTAIR may promote dedifferentiation of lung epithelial cells (69). Forced expression of HOTAIR in non-transformed breast and lung cancer cell lines has been shown to promote growth in Figure 1.…”

Section: Hox Antisense Intergenic Rna (Hotair)mentioning

confidence: 99%

Long Non-coding RNAs and their Role in Metastasis

Weidle

Birzele

Kollmorgen

et al. 2017

CGP

171

124

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Abstract.Metastasis is the major cause of death in patients with cancer. It is mediated by a multi-step process referred to as the metastatic cascade (1, 2). Initial steps include local invasion and migration, angiogenesis, epithelialmesenchymal transition (EMT) and intravasation. Tumor cells enter the circulation as single cells or circulating tumor cell clusters, are coated by platelets to escape an immune response and subsequently arrest in capillaries in distant organs as a prerequisite for extravasation. Colonization starts by homing of tumor cells in supporting niches of the organ parenchyma, followed by a latency phase which can last from several months to decades. A prerequiste for overt outgrowth of micrometastases is their adaptation to the local microenvironment and acquisition of colonisation-promoting traits (3-6). The pattern of colonized distant organs depends on the tumor type and can range from predominant spread to one organ and colonization of different types of organs sequentially or simultaneously (7). Several genes and their products have been identified to mediate crucial steps of the metastatic process such as metastasis initiation and progression, as well as organ-specific functions of metastasis (virulence) (8, 9). These gene products include proteases, chemokines, cytokines and their receptors, angiogenic factors, intracellular and transmembrane kinases, adhesion molecules, components of the extracellular matrix (ECM), GPI-linked receptors and carbohydrate metabolism-related enzymes (8, 9). More recently, an important impact of RNA-related molecules for metastasis has emerged. MicroRNAs (miRs) and other types of RNA modulate metastasis via regulatory networks (10,11). In this review we focus on the role of long non-coding RNAs (lncRNA) as promoters or inhibitors of metastasis in different tumor entities since there is an urgent need to define new targets for therapeutic intervention. With the exception of denosumab for treatment of bone metastases, all other agents evaluated in clinical studies for treatment of metastatic disease gave rise to mixed or disappointing results (6).

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“…In a mouse model of SCA1, a modest exercise regimen extends longevity by reducing CIC levels in the brainstem. CIC loss through genetic perturbation also mitigates multiple SCA1 phenotypes in this model (Fryer et al 2011). …”

Section: Spinocerebellar Ataxia Typementioning

confidence: 99%

CIC (capicua transcriptional repressor)

Firme¹,

Marra²

2017

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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CIC is a tissue-specific transcriptional repressor that is highly conserved between metazoan organisms and is required for the normal development of multiple adult structures. CIC functions to transduce receptor tyrosine kinase (RTK) signalling into gene expression changes through a mechanism termed default repression, wherein CIC is bound to target gene promoters or enhancers and inhibits transcription in the absence of signal. This CIC-DNA interaction can be inhibited through activation of the RTK core signalling molecule mitogen-activated protein kinase (MAPK), which then allows for the transcription of CIC targets through this RTK-MAPK signalling axis. Components of RTK signalling are commonly dysregulated in cancers, possibly implying that CIC alterations observed in specific cancer types (e.g. oligodendroglioma and Ewing-like sarcomas) are a form of RTK signalling dysregulation that drives oncogenesis. CIC is also specifically expressed in cells of the developing central nervous system and its dysfunction is associated with the neurodegenerative disorder spinocerebellar ataxia type 1, implicating CIC in neuronal cell development and/or homeostasis. Other possible cellular and physiological roles for CIC include cell cycle control, ATP-citrate lyase phosphorylation, reactive oxygen species homeostasis, and bile acid homeostasis.

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ATXN1 Protein Family and CIC Regulate Extracellular Matrix Remodeling and Lung Alveolarization

Cited by 93 publications

References 48 publications

Torso RTK controls Capicua degradation by changing its subcellular localization

Torso RTK controls Capicua degradation by changing its subcellular localization

Long Non-coding RNAs and their Role in Metastasis

CIC (capicua transcriptional repressor)

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