Protein Kinase B Localization and Activation Differentially Affect S6 Kinase 1 Activity and Eukaryotic Translation Initiation Factor 4E-Binding Protein 1 Phosphorylation

Dufner, Almut; Andjelković, Mirjana; Burgering, Boudewijn M.T.; Hemmings, Brian A.; Thomas, George

doi:10.1128/mcb.19.6.4525

Cited by 167 publications

(153 citation statements)

References 61 publications

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“…PI3K-dependent activation of S6K1 is mediated by a variety of effectors, including PDK1, Akt, PKCz and l, and the small G proteins Cdc42 and Rac1 (Chou and Blenis, 1996;Alessi et al, 1998;Pullen et al, 1998;Dufner et al, 1999;Romanelli et al, 1999;and reviewed in Martin and Blenis, 2002). The best understood phosphorylation event on S6K1 is the direct phosphorylation of threonine 229, which lies in the activation loop of the kinase domain, by PDK1 (Alessi et al, 1998;Pullen et al, 1998).…”

Section: Signaling To S6k1: Regulation Of Ribosome Biogenesis?mentioning

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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Section: Signaling To S6k1: Regulation Of Ribosome Biogenesis?mentioning

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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“…The PI3K/Akt pathway can also phosphorylate and activate CREB which regulates transcription of Mcl-1 and B cell leukemia-2 Bcl-2 (Du et al, 1998, Arcinas et al, 2001. The PI3K/Akt pathway also regulates the mammalian target of rapamycin (mTOR) and ribosomal protein kinases such as p70 ribosomal six kinase (p70S6K) (Mahalingam et al, 1996, Dufner et al, 1999, Romanelli et al, 1999, Harada et al, 2001, Edinger et al, 2004, Panwalker et al, 2004, Jonassen et al, 2004) (see Below). It is worth noting that Akt can cause the activation of specific substrates (e.g., IκKα and CREB) or may mediate the inactivation of other proteins (e.g., Raf-1, B-Raf [by the Akt related kinase serum glucocorticoid kinase (SGK)], p21 Bim,Bad,Foxo3a,).…”

Section: Overview Of the Pi3k/pten/akt/mtor And Raf/mek/erk Pathways mentioning

confidence: 99%

Alteration of Akt activity increases chemotherapeutic drug and hormonal resistance in breast cancer yet confers an achilles heel by sensitization to targeted therapy

McCubrey

Sokolosky

Lehmann

et al. 2008

Advances in Enzyme Regulation

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The PI3K/PTEN/Akt/mTOR pathway plays critical roles in the regulation of cell growth. The effects of this pathway on drug resistance and cellular senescence of breast cancer cells has been a focus of our laboratory. Introduction of activated Akt or mutant PTEN constructs which lack lipid phosphatase [PTEN(G129E)] or lipid and protein phosphatase [PTEN(C124S)] activity increased the resistance of the cells to the chemotherapeutic drug doxorubicin, and the hormonal drug tamoxifen. Activated Akt and PTEN genes also inhibited the induction of senescence after doxorubicin treatment; a phenomenon associated with unrestrained proliferation and tumorigenesis. Interference with the lipid phosphatase domain of PTEN was sufficient to activate Akt/mTOR/p70S6K as MCF-7 cells transfected with the mutant PTEN gene lacking the lipid phosphatase activity [PTEN(G129E)] displayed elevated levels of activated Akt and p70S6K compared to empty vector transfected cells. Cells transfected with mutant PTEN or Akt constructs were hypersensitive to mTOR inhibitors when compared with the parental or empty vector transfected cells. Akt-transfected cells were cultured for over two months in tamoxifen from which tamoxifen and doxorubicin resistant cells were isolated that were >10-fold more resistant to tamoxifen and doxorubicin than the original Akt-transfected cells. These cells had a decreased induction of both activated p53 and total p21 Cip1 upon doxorubicin treatment. Furthermore, these cells had an increased inactivation of GSK-3β and decreased expression of the estrogen receptor-α. In these drug resistant cells, there was an increased activation Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errorsmaybe discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. of ERK which is associated with proliferation. These drug resistant cells were hypersensitive to mTOR inhibitors and also sensitive to MEK inhibitors, indicating that the enhanced p70S6K and ERK expression was relevant to their drug and hormonal resistance. Given that Akt is overexpressed in greater than 50% of breast cancers, our results point to potential therapeutic targets, mTOR and MEK. These studies indicate that activation of the Akt kinase or disruption of the normal activity of the PTEN phosphatase can have dramatic effects on activity of p70S6K and other downstream substrates and thereby altering the therapeutic sensitivity of breast cancer cells. The effects of doxorubicin and tamoxifen on induction of the Raf/MEK/ERK and PI3K/Akt survival pathways were examined in unmodified MCF-7 breast cells. Doxorubicin was a potent inducer of activated ERK and to a lesser extent Akt. Tamoxifen also in...

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“…In this manner rapamycin blocks cap-dependent initiation of translation. The mTOR, therefore, links the PI3K pathway to translational regulation (22,25,26). mRNAs encoding growth factors, cytokines, transcription factors, and regulators of apoptosis characteristically are regulated by cap-dependent translational control (27).…”

Section: Cd28 Regulates the Translation Of Bcl-x L Via Thementioning

confidence: 99%

CD28 Regulates the Translation of Bcl-xL via the Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Pathway

Rose

Chen

et al. 2005

The Journal of Immunology

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In concert with the TCR, CD28 promotes T cell survival by regulating the expression of the antiapoptotic protein Bcl-xL. The mechanism by which CD28 mediates the induction of Bcl-xL remains unknown. We show that although signaling through the TCR is sufficient to stimulate transcription of Bcl-xL mRNA, CD28, by activating PI3K and mammalian target of rapamycin, provides a critical signal that regulates the translation of Bcl-xL transcripts. We observe that CD28 induced 4E-binding protein-1 phosphorylation, an inhibitor of the translational machinery, and that CD28 costimulation directly augmented the translation of a Bcl-xL 5′-untranslated region reporter construct. Lastly, costimulation by CD28 shifted the distribution of Bcl-xL mRNA transcripts from the pretranslation complex to the translationally active polyribosomes. These results demonstrate that CD28 relieves the translational inhibition of Bcl-xL in a PI3K/mammalian target of rapamycin-dependent manner.

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Protein Kinase B Localization and Activation Differentially Affect S6 Kinase 1 Activity and Eukaryotic Translation Initiation Factor 4E-Binding Protein 1 Phosphorylation

Cited by 167 publications

References 61 publications

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

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

Alteration of Akt activity increases chemotherapeutic drug and hormonal resistance in breast cancer yet confers an achilles heel by sensitization to targeted therapy

CD28 Regulates the Translation of Bcl-xL via the Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Pathway

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