The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners

Rosner, Margit; Hanneder, Michaela; Siegel, Nicol; Valli, Alessandro; Hengstschläger, Markus

doi:10.1016/j.mrrev.2008.01.001

Cited by 127 publications

(89 citation statements)

References 79 publications

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“…However, it has previously been shown that TSC1 and TSC2 bind multiple other proteins, suggesting that the functions of the TSC1:TSC2 complex are broader (Rosner et al, 2008). This indicates that so far unknown effects of TSC mutations could affect the clinical phenotype of TSC patients.…”

Section: Synopsismentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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Section: Synopsismentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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“…TSC1 protein has many binding partners in addition to TSC2, and is essential for mouse embryonic development [22][23][24] . Recently, it has been shown that TSC1 has critical roles in neurodevelopment and neurological diseases, immune diseases, diabetes, autophagy and DNA repair [25][26][27][28] .…”

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confidence: 99%

“…Given the large size of the TSC1 protein, it is quite striking that this short TSC1 region accounts for all known pathogenic TSC1 mutations. TSC1-NTD is conserved among all TSC1 proteins, including that from S. pombe, and may contribute to its interactions with TSC1 partners, in addition to TSC1 stability 22,35 .…”

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confidence: 99%

Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations

et al. 2013

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Tuberous sclerosis complex is a disease caused by mutations in two tumor-suppressor genes, TSC1 and TSC2. The TSC1 protein, also known as hamartin, has a critical role in controlling mTOR signalling. TSC1 does not bear apparent sequence homology with other proteins. Here we show that the N-terminal half of yeast TSC1 forms a protease-resistant domain, which is evolutionarily conserved. The crystal structure of this yeast TSC1 core domain shows that it contains a pseudo-HEAT repeat fold with its C-terminal end capped by a helical subdomain. This allows us to model the three-dimensional structure of the human TSC1 N-terminal domain (TSC1-NTD), which anchors essentially all pathogenic TSC1 missense mutations found in tuberous sclerosis patients. Interestingly, most pathogenic mutations map inside of the folded TSC1-NTD structure, whereas most non-pathogenic variants are on the structural surface. This indicates that the disruption of the TSC1-NTD globular structure is a major cause of tuberous sclerosis.

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“…In this regard, the MKK2/p38 complex exported from the nucleus appears to interact with a cytoplasmic HSP27/Akt complex (Wu et al, 2007). Similarly to Akt, also MKK2 impinges on both protein synthesis and catabolism, by phosphorylating molecules involved in the two pathways (reviewed in Rosner et al, 2008). However, despite p38 appears involved in the pathogenesis of muscle…”

Section: Strategies To Correct Metabolic Alterationsmentioning

confidence: 99%

Mechanism-Based Therapeutic Approaches to Cachexia

et al. 2013

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Cachexia is a multifactorial syndrome characterized by body weight loss, depletion of adipose tissue and skeletal muscle mass, and marked alterations of the metabolic homeostasis.The occurrence of cachexia significantly impinges on patient's morbidity and mortality, and on quality of life. Inflammation, anorexia/malnutrition, alterations of protein and lipid metabolism are among the main mechanisms involved in the development of cachexia. While anorexia and malnutrition are long known contributing factors, the mechanisms leading to inflammation and metabolic alterations were clarified later on. On these premises, several therapeutic approaches were proposed. Most of them are in the pre-clinical phase, but some already reached the clinical experimentation. The present review will focus on treatment options proposed on the basis of mechanistic alterations. In this regard, in addition to nutritional and anti-inflammatory strategies, also approaches based on perturbation of specific signal transduction pathways are taken into consideration.

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The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners

Cited by 127 publications

References 79 publications

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations

Mechanism-Based Therapeutic Approaches to Cachexia

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