Biomaterial Database

Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice. 2022

Xiaofang Shi, and S Joseph Endicott, and Richard A Miller

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Downregulation of mTOR (mechanistic target of rapamycin) can extend lifespan in multiple species, including mice. Growth hormone receptor knockout mice (GHRKO) and Snell dwarf mice have 40% or greater lifespan increase, and have lower mTORC1 function, which might reflect alteration in mTORC1 components or alteration of upstream proteins that modulate mTOR activity. Here we report reduction of mTORC components DEPTOR and PRAS40 in liver of these long-lived mice; these changes are opposite in direction to those that would be expected to lead to lower mTORC1 function. In contrast, levels of the upstream regulators TSC1 and TSC2 are elevated in GHRKO and Snell liver, kidney and skeletal muscle, and the ratio of phosphorylated TSC2 to total TSC2 is lower in the tissues of the long-lived mutant mice. In addition, knocking down TSC2 in GHRKO fibroblasts reversed the effects of the GHRKO mutation on mTORC1 function. Thus increased amounts of unphosphorylated, active, inhibitory TSC may contribute to lower mTORC1 function in these mice.

UI	MeSH Term	Description	Entries
D011986	Receptors, Somatotropin	Cell surface proteins that bind GROWTH HORMONE with high affinity and trigger intracellular changes influencing the behavior of cells. Activation of growth hormone receptors regulates amino acid transport through cell membranes, RNA translation to protein, DNA transcription, and protein and amino acid catabolism in many cell types. Many of these effects are mediated indirectly through stimulation of the release of somatomedins.	Growth Hormone Receptors,Receptors, Growth Hormone,Somatomammotropin Receptors,Somatotropin Receptors,Growth Hormone Receptor,Receptor, Growth Hormone,Receptors, Somatomammotropin,Somatomammotropin Receptor,Somatotropin Receptor,Hormone Receptor, Growth,Hormone Receptors, Growth
D000076222	Mechanistic Target of Rapamycin Complex 1	An evolutionarily conserved multiprotein complex that functions as a cellular energy sensor and regulator of protein synthesis for cell growth and proliferation. It consists of TOR SERINE-THREONINE KINASES; REGULATORY-ASSOCIATED PROTEIN OF MTOR (RAPTOR); MLST8 PROTEIN; and AKT1 substrate 1 protein. The activity of the complex is regulated by SIROLIMUS; INSULIN; GROWTH FACTORS; PHOSPHATIDIC ACIDS; some amino acids or amino acid derivatives, and OXIDATIVE STRESS.	TOR Complex 1,TORC1,Target of Rapamycin Complex 1,mTORC1,mTORC1 Complex,Complex, mTORC1
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D058570	TOR Serine-Threonine Kinases	A serine threonine kinase that controls a wide range of growth-related cellular processes. The protein is referred to as the target of RAPAMYCIN due to the discovery that SIROLIMUS (commonly known as rapamycin) forms an inhibitory complex with TACROLIMUS BINDING PROTEIN 1A that blocks the action of its enzymatic activity.	TOR Kinase,TOR Kinases,TOR Serine-Threonine Kinase,Target of Rapamycin Protein,mTOR Serine-Threonine Kinase,mTOR Serine-Threonine Kinases,FK506 Binding Protein 12-Rapamycin Associated Protein 1,FKBP12-Rapamycin Associated Protein,FKBP12-Rapamycin Complex-Associated Protein,Mammalian Target of Rapamycin,Mechanistic Target of Rapamycin Protein,RAFT-1 Protein,Rapamycin Target Protein,Target of Rapamycin Proteins,mTOR Protein,FK506 Binding Protein 12 Rapamycin Associated Protein 1,FKBP12 Rapamycin Associated Protein,FKBP12 Rapamycin Complex Associated Protein,Kinase, TOR,Kinase, TOR Serine-Threonine,Kinase, mTOR Serine-Threonine,Kinases, TOR Serine-Threonine,Kinases, mTOR Serine-Threonine,Protein Target, Rapamycin,Protein, RAFT-1,Protein, mTOR,RAFT 1 Protein,Rapamycin Protein Target,Serine-Threonine Kinase, TOR,Serine-Threonine Kinase, mTOR,Serine-Threonine Kinases, TOR,Serine-Threonine Kinases, mTOR,TOR Serine Threonine Kinase,TOR Serine Threonine Kinases,mTOR Serine Threonine Kinase,mTOR Serine Threonine Kinases
D018345	Mice, Knockout	Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes.	Knockout Mice,Mice, Knock-out,Mouse, Knockout,Knock-out Mice,Knockout Mouse,Mice, Knock out
D020123	Sirolimus	A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to IMMUNOPHILINS. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties.	Rapamycin,AY 22-989,I-2190A,Rapamune,AY 22 989,AY 22989,I 2190A,I2190A