A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells

Kwiatkowski, David J.; Zhang, Hongbing; Bandura, Jennifer L.; Heiberger, Kristina M.; Glogauer, Michael; El-Hashemite, Nisreen; Onda, Hiroaki

doi:10.1093/hmg/11.5.525

Cited by 606 publications

(574 citation statements)

References 38 publications

Supporting

Mentioning

542

Contrasting

Unclassified

Order By: Relevance

“…Ped6b H620Q /Pde6b H620Q mice were rederived via oviduct transfer using the European Mouse Mutant Archive (EMMA) morulae (22,44); Pde6g CreERT2 mice were generated in the Barbara & Donald Jonas Stem Cell & Regenerative Medicine Laboratory (45-51); and Tsc1 tm1Djk /J were purchased from the Jackson Laboratory (Stock No. 005680) (52). All mice were housed in the Columbia University Pathogen-free Eye Institute Annex Animal Care Services Facility and maintained with a 12-h light/ 12-h dark cycle.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa

Zhang

Justus

et al. 2016

Hum. Mol. Genet.

View full text Add to dashboard Cite

Retinitis pigmentosa (RP) is an incurable neurodegenerative condition featuring photoreceptor death that leads to blindness. Currently, there is no approved therapeutic for photoreceptor degenerative conditions like RP and atrophic age-related macular degeneration (AMD). Although there are promising results in human gene therapy, RP is a genetically diverse disorder, such that gene-specific therapies would be practical in a small fraction of patients with RP. Here, we explore a non-genespecific strategy that entails reprogramming photoreceptors towards anabolism by upregulating the mechanistic target of rapamycin (mTOR) pathway. We conditionally ablated the tuberous sclerosis complex 1 (Tsc1) gene, an mTOR inhibitor, in the rods of the Pde6b H620Q/H620Q preclinical RP mouse model and observed, functionally and morphologically, an improvement in the survival of rods and cones at early and late disease stages. These results elucidate the ability of reprogramming the metabolome to slow photoreceptor degeneration. This strategy may also be applicable to a wider range of neurodegenerative diseases, as enhancement of nutrient uptake is not gene-specific and is implicated in multiple pathologies. Enhancing

show abstract

Section: Discussionmentioning

confidence: 99%

Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa

Zhang

Justus

et al. 2016

Hum. Mol. Genet.

View full text Add to dashboard Cite

show abstract

“…In contrast, under stress conditions such as energy depletion resulting in an increased AMP to ATP ratio, the protein kinase AMPK is activated through phosphorylation by upstream kinases, such as LKB1 (Hardie, Ross, & Hawley, 2012), and phosphorylates TSC2 to enhance its GAP activity (Inoki, Zhu, & Guan, 2003). Thus, since the TSC complex integrates multiple upstream signals to negatively regulate a key step in mTORC1 activation, its disruption causes constitutive mTORC1 activation (Byles et al, 2013; Castets et al, 2013; Kwiatkowski et al, 2002). …”

Section: Mtor and Metabolismmentioning

confidence: 99%

Myelination and mTOR

Figlia

Gerber

Suter

2017

Glia

136

120

View full text Add to dashboard Cite

Myelinating cells surround axons to accelerate the propagation of action potentials, to support axonal health, and to refine neural circuits. Myelination is metabolically demanding and, consistent with this notion, mTORC1—a signaling hub coordinating cell metabolism—has been implicated as a key signal for myelination. Here, we will discuss metabolic aspects of myelination, illustrate the main metabolic processes regulated by mTORC1, and review advances on the role of mTORC1 in myelination of the central nervous system and the peripheral nervous system. Recent progress has revealed a complex role of mTORC1 in myelinating cells that includes, besides positive regulation of myelin growth, additional critical functions in the stages preceding active myelination. Based on the available evidence, we will also highlight potential nonoverlapping roles between mTORC1 and its known main upstream pathways PI3K‐Akt, Mek‐Erk1/2, and AMPK in myelinating cells. Finally, we will discuss signals that are already known or hypothesized to be responsible for the regulation of mTORC1 activity in myelinating cells.

show abstract

“…In mice, homozygous loss of either Tsc1 or Tsc2 result in embryonic lethality, whereas in heterozygous animals increased tumor formation including renal cystadenomas, and learning deficits are apparent (Rennebeck et al, 1998;Kobayashi et al, 1999;Kwiatkowski et al, 2002). Additionally, epilepsy, brain malformations, RCCs and additional tumors have been described in Eker rats, which have a naturally occurring inactivating Tsc2 mutation (Cook and Walker, 2004;Hino, 2004;Yeung, 2004).…”

Section: Nf1mentioning

confidence: 99%

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

et al. 2011

View full text Add to dashboard Cite

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.

show abstract

A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells

Cited by 606 publications

References 38 publications

Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa

Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa

Myelination and mTOR

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

Contact Info

Product

Resources

About