FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse

Hentges, Kathryn E.; Sirry, Baheya; Gingeras, Anne Claude; Sarbassov, Dos D.; Sonenberg, Nahum; Sabatini, David M.; Peterson, Andrew S.

doi:10.1073/pnas.241184198

Cited by 159 publications

(157 citation statements)

References 22 publications

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Section: Discussionmentioning

confidence: 99%

“…mTOR is normally expressed by progenitors in the developing telencephalon (Hentges et al, 2001). In the mouse mutant flat-top, mTOR function in the developing telencephalon is reduced, as is proliferation (Hentges et al, 1999(Hentges et al, , 2001. A similar phenotype was observed after rapamycin treatment in utero at early stages of development (Hentges et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…It is expressed in embryonic cortical cells (Hentges et al, 2001), and it is phosphorylated at the Akt site (Ser2448) in response to EGF-FGF2-insulin in control and Akt-infected cortical cells (data not shown). Akt can also increase mTOR activity indirectly by phosphorylating and inhibiting tsc2, a negative regulator of mTOR (Manning et al, 2002).…”

Section: Akt-1 Does Not Depend On P21(cip1) To Regulate Progenitor Ormentioning

confidence: 94%

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Akt-1 Expression Level Regulates CNS Precursors

Sinor¹,

Lillien²

2004

J. Neurosci.

109

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Although most cells in the embryonic mouse cortex express the serine-threonine kinase Akt-1, a small population of progenitors expresses Akt-1 protein at a higher level. To determine the functional significance of this difference, we used a retrovirus to increase Akt-1 expression in cortical progenitors. Increased Akt expression enhanced Akt activation after growth factor stimulation of progenitors. In vivo, it promoted retention in progenitor layers, the ventricular zone and subventricular zone. In vitro, it enhanced proliferation and survival, but did not impair migration. Moreover, it increased the proportion of stem cells, defined by a self-renewal assay. These effects did not depend on the Akt substrate p21(Cip1). In contrast, rapamycin, an inhibitor of mTOR (mammalian target of rapamycin), altered effects of elevated Akt-1 selectively: it eliminated the increase in stem cells and reduced the proliferative response, but had no effect on survival. The ability of elevated Akt-1 to increase the self-renewing population therefore depends on a rapamycin-sensitive mechanism (presumably inhibition of mTOR activity) but not on p21(Cip1), and can be distinguished from its effects on the proliferation and survival of other types of progenitors. Our findings suggest that expression of a high level of Akt-1 by a subpopulation of cortical progenitors biases their responses to extrinsic signals to increase their survival, proliferation, and/or self-renewal. Heterogeneity in Akt-1 level among progenitors could therefore allow cells that share a microenvironment to respond differently to the same extrinsic signals.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Akt-1 Does Not Depend On P21(cip1) To Regulate Progenitor Ormentioning

confidence: 94%

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Akt-1 Expression Level Regulates CNS Precursors

Sinor¹,

Lillien²

2004

J. Neurosci.

109

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“…The Akt/mTOR pathway has been shown to regulate cell-cycle progression, as inhibition of this pathway can result in G1 cell-cycle arrest (Wiederrecht et al, 1995;Hentges et al, 2001). We have previously shown that U-251 cells treated with PMA for 24 h resulted in a striking increase in PKC-Z protein levels (Hussaini et al, 2000).…”

Section: H-thymidine Uptakementioning

confidence: 98%

PKC-η mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways

et al. 2004

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“…Moreover, it is imperative to identify the downstream targets and cellular processes that are regulated by TOR. TOR function is clearly vitally important in mammals, as homozygous mTOR inactivation in the mouse is embryonically lethal (Hentges et al, 2001).…”

Section: Future Directionsmentioning

confidence: 99%

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

2004

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Cell growth (an increase in cell mass and size through macromolecular biosynthesis) and cell cycle progression are generally tightly coupled, allowing cells to proliferate continuously while maintaining their size. The target of rapamycin (TOR) is an evolutionarily conserved kinase that integrates signals from nutrients (amino acids and energy) and growth factors (in higher eukaryotes) to regulate cell growth and cell cycle progression coordinately. In mammals, TOR is best known to regulate translation through the ribosomal protein S6 kinases (S6Ks) and the eukaryotic translation initiation factor 4E-binding proteins. Consistent with the contribution of translation to growth, TOR regulates cell, organ, and organismal size. The identification of the tumor suppressor proteins tuberous sclerosis1 and 2 (TSC1 and 2) and Ras-homolog enriched in brain (Rheb) has biochemically linked the TOR and phosphatidylinositol 3-kinase (PI3K) pathways, providing a mechanism for the crosstalk that occurs between these pathways. TOR is emerging as a novel antitumor target, since the TOR inhibitor rapamycin appears to be effective against tumors resulting from aberrantly high PI3K signaling. Not only may inhibition of TOR be effective in cancer treatment, but rapamycin is an FDA-approved immunosuppressive and cardiology drug. We review here what is known (and not known) about the function of TOR in cellular and animal physiology.

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FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse

Cited by 159 publications

References 22 publications

Akt-1 Expression Level Regulates CNS Precursors

Akt-1 Expression Level Regulates CNS Precursors

PKC-η mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

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