TSC2: filling the GAP in the mTOR signaling pathway

Li, Yong; Corradetti, Michael N.; Inoki, Ken; Guan, Kun Liang

doi:10.1016/j.tibs.2003.11.007

Cited by 388 publications

(298 citation statements)

References 75 publications

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“…5,6,12,28 In this study, diosgenin downregulated the expression of pAkt, suggesting diosgenin inhibits Akt-mediated survival signaling in BCa cells. Similar effects have been observed in previous studies, 29 and indicate diosgenin inhibits Akt in other types of cancers.…”

Section: Discussionsupporting

confidence: 54%

Diosgenin targets Akt‐mediated prosurvival signaling in human breast cancer cells

Srinivasan

Koduru

Kumar

et al. 2009

Intl Journal of Cancer

131

105

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In recent years, Akt signaling has gained recognition for its functional role in more aggressive, therapy‐resistant malignancies. As it is frequently constitutively active in cancer cells, several drugs are being investigated for their ability to inhibit Akt signaling. The purpose of this study is to determine effect of diosgenin (fenugreek), a dietary compound on Akt signaling and its downstream targets on estrogen receptor positive (ER+) and estrogen receptor negative (ER−) breast cancer (BCa) cells. Diosgenin inhibits pAkt expression and Akt kinase activity without affecting PI3 kinase levels, resulting in the inhibition of its downstream targets, NF‐κB, Bcl‐2, survivin and XIAP. The Raf/MEK/ERK pathway, another functional downstream target of Akt, was inhibited by diosgenin in ER+ but not in ER− BCa cells. Additionally, we found that diosgenin caused G1 cell cycle arrest by downregulating cyclin D1, cdk‐2 and cdk‐4 expression in both ER+ and ER− BCa cells resulting in the inhibition of cell proliferation and induction of apoptosis. Interestingly, no significant toxicity was seen in the normal breast epithelial cells (MCF‐10A) following treatment with diosgenin. Additionally, in vivo tumor studies indicate diosgenin significantly inhibits tumor growth in both MCF‐7 and MDA‐231 xenografts in nude mice. Thus, these results suggest that diosgenin might prove to be a potential chemotherapeutic agent for the treatment of BCa. © 2009 UICC

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Section: Discussionsupporting

confidence: 54%

Diosgenin targets Akt‐mediated prosurvival signaling in human breast cancer cells

Srinivasan

Koduru

Kumar

et al. 2009

Intl Journal of Cancer

131

105

View full text Add to dashboard Cite

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“…Akt plays an unusual role in mTOR signaling because it acts upstream of mTORC1 and downstream of mTORC2. Akt controls mTORC1 in part through tuberous sclerosis complex (TSC) 2, a protein that has GTPase-activating protein (GAP) activity toward Rheb, a small GTP-binding protein related to Ras [15]. TSC2 forms a tight complex with TSC1.…”

Section: Mtor Signal Transduction and Cellular Functionsmentioning

confidence: 99%

Rapamycin and mTOR kinase inhibitors

2008

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Mammalian target of rapamycin (mTOR) is a protein kinase that controls cell growth, proliferation, and survival. mTOR signaling is often upregulated in cancer and there is great interest in developing drugs that target this enzyme. Rapamycin and its analogs bind to a domain separate from the catalytic site to block a subset of mTOR functions. These drugs are extremely selective for mTOR and are already in clinical use for treating cancers, but they could potentially activate an mTOR-dependent survival pathway that could lead to treatment failure. By contrast, small molecules that compete with ATP in the catalytic site would inhibit all of the kinase-dependent functions of mTOR without activating the survival pathway. Several non-selective mTOR kinase inhibitors have been described and here we review their chemical and cellular properties. Further development of selective mTOR kinase inhibitors holds the promise of yielding potent anticancer drugs with a novel mechanism of action.

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“…[5][6][7] mTORC1 is an important element in controlling cell proliferation and growth, insulin signaling, and protein translation. 8 Dysregulation of mTORC1 is an important aspect in the pathogenesis of TSC. 9 Somatic mutation of the second TSC1 or TSC2 allele leads to a loss of heterozygosity, upregulation of mTOR, and dysregulated cellular metabolism.…”

confidence: 99%

Self-reported reproductive health in women with tuberous sclerosis complex

Gabitzsch

Hashmi

Koenig

et al. 2013

Genetics in Medicine

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Tuberous sclerosis complex (TSC) is an autosomal-dominant tumor-suppressor disorder characterized by the development of hamartomas in many organ systems. The prevalence of TSC is estimated at 1 in 6,000 individuals, and up to 70% of cases are due to de novo mutation. 1,2 Inactivating mutations in either the TSC1 or TSC2 gene, which encode the proteins hamartin and tuberin, respectively, cause TSC. 3,4 These proteins form a heterodimer involved in negative regulation of the mammalian target of rapamycin complex 1 (mTORC1) kinase. 5-7 mTORC1 is an important element in controlling cell proliferation and growth, insulin signaling, and protein translation. 8 Dysregulation of mTORC1 is an important aspect in the pathogenesis of TSC. 9 Somatic mutation of the second TSC1 or TSC2 allele leads to a loss of heterozygosity, upregulation of mTOR, and dysregulated cellular metabolism. 9 Although virtually any organ can be affected in TSC, the brain, skin, kidneys, heart, and lungs are the principal sites of pathology. TSC shows no ethnic or sex predilection, but interestingly, sex-specific manifestations have been described. Almost 40% of women with TSC develop the pulmonary manifestation lymphangioleiomyomatosis, typically between the ages of 20 and 40 years; most men are unaffected. 10,11 Moreover, the most common renal manifestation, angiomyolipoma, impacts more than 70% of patients, 2 but females are affected an estimated three to four times more often than males. 12 Lymphangioleiomyomatosis and angiomyolipomas share histological features and express estrogen and progesterone receptors, considered important in development. 13 Other effects of sex hormones or reproductive manifestations in TSC are poorly understood.Intriguingly, the role of the TSC1 and TSC2 genes in normal organ function and TSC-associated pathogenesis came to light from the creation of a variety of organ-specific Tsc1-or Tsc2-null animals. Recently, the use of conditional knockout models revealed a role for the murine Tsc1 and Tsc2 genes in the reproductive functioning of the ovary. 14,15 Specifically, these genes are crucial for the maintenance of primordial follicles in a quiescent state and appropriate activation throughout the murine reproductive period. Deletions of either the Tsc1 or Tsc2 gene in the ovaries of mice led to a premature activation of primordial follicles and subsequent depletion of the entire follicular pool, despite initial intact reproductive maturation. The mice essentially experienced what would be defined in humans as premature ovarian insufficiency (POI). POI represents a clear disruption in the normal female reproductive life span and is defined as the cessation of menses in a woman younger than 40 years. POI affects an estimated 1% of the females in the US Purpose: Little is known about sex-specific manifestations of tuberous sclerosis complex. Inactivating mutations in the TSC1 and TSC2 genes cause tuberous sclerosis complex, and recent evidence points to a crucial role for these genes in maintaining appropriate ovarian fun...

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TSC2: filling the GAP in the mTOR signaling pathway

Cited by 388 publications

References 75 publications

Diosgenin targets Akt‐mediated prosurvival signaling in human breast cancer cells

Diosgenin targets Akt‐mediated prosurvival signaling in human breast cancer cells

Rapamycin and mTOR kinase inhibitors

Self-reported reproductive health in women with tuberous sclerosis complex

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