PDK1 regulates growth through Akt and S6K in
            <i>Drosophila</i>

Rintelen, Felix; Stocker, Hugo; Thomas, George; Hafen, Ernst

doi:10.1073/pnas.011318098

Cited by 158 publications

(145 citation statements)

References 41 publications

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“…The disparity between results reported here and those of Pekarsky et al (23) could indicate a cell type or transformation-state dependence on the outcome of TCL1 overexpression in regulating p70S6 kinase activity. Membrane-linked AKT has been shown to directly activate p70S6 kinase, whereas PDK1 phosphorylates p70S6 kinase when AKT is cytosol-restricted (42)(43)(44). Recently, we have shown that AKT and TCL1 interact optimally at the cytoplasmic membrane in transformed B cells (45).…”

Section: Discussionmentioning

confidence: 99%

DysregulatedTCL1promotes multiple classes of mature B cell lymphoma

Hoyer

French

Turner

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

104

110

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The TCL1 protooncogene is overexpressed in many mature B cell lymphomas, especially from AIDS patients. To determine whether aberrant expression promotes B cell transformation, we generated a murine model in which a TCL1 transgene was overexpressed at similar levels in both B and T cells. Strikingly, transgenic mice developed Burkitt-like lymphoma (BLL) and diffuse large B cell lymphoma (DLBCL) with attendant Bcl-6 expression and mutated J H gene segments at a very high penetrance beginning at 4 months of age. In contrast, only one mouse developed a T cell malignancy at 15 months, consistent with a longer latency for transformation of T cells by TCL1. Activation of premalignant splenic B cells by means of B cell antigen receptor (BCR) engagement resulted in significantly increased proliferation and augmented AKT-dependent signaling, including increased S6 ribosomal protein phosphorylation. Transgenic spleen cells also survived longer than wild-type spleen cells in long-term culture. Together these data demonstrate that TCL1 is a powerful oncogene that, when overexpressed in both B and T cells, predominantly yields mature B cell lymphomas.T he TCL1 (T cell leukemia 1) protooncogene is expressed in CD3 Ϫ CD4 Ϫ CD8 Ϫ precursor T cells and is extinguished at the CD4 ϩ CD8 ϩ stage of thymocyte development (1). In B cells, TCL1 is first expressed in pro-B cells and remains high in naive mantle zone B cells of peripheral lymphoid tissues (1-4). Downregulation of TCL1 expression in follicle center centroblasts and centrocytes is followed by gene extinction in post-germinal center (GC) memory B cells and plasma cells (4, 5).Continued high-level TCL1 expression, because of chromosomal rearrangements, was implicated in mature peripheral T cell malignancies (6, 7). Polyclonal and oligoclonal T cell expansions preceded clonal outgrowth by many years, suggesting that additional lesions were required for transformation (8,9). Supporting this tumorigenic mechanism, transgenic mice expressing TCL1-familymember proteins exclusively in T cells developed polyclonal T cell expansions before the evolution of clonal malignancies at 15 to 20 months (10, 11). Overexpression of TCL1, or MTCP1 (mature T cell proliferation 1), in mouse T cells did not affect B cell development or produce B cell lymphomas. These findings indicate that aberrant expression of TCL1 or MTCP1 in T cells perturbs T cell homeostasis through cell autonomous pathways without inducing premalignant or malignant changes in bystander B cells.About 15% of AIDS patients develop aggressive B cell nonHodgkin lymphoma (AIDS-NHL) (12, 13). Most AIDS-NHL originate from GC or post-GC B cells, but the early events leading to AIDS-NHL remain poorly defined (13,14). Diffuse large B cell lymphoma (DLBCL) is the most prevalent type of AIDS-NHL, and these tumors generally lack consistent genetic and͞or viral tumorpromoting alterations. Recently, abundant TCL1 expression was shown in a high percentage of AIDS-NHL of post-GC origin (3,4). This discovery led us to postulate that TCL1 dy...

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Section: Discussionmentioning

confidence: 99%

DysregulatedTCL1promotes multiple classes of mature B cell lymphoma

Hoyer

French

Turner

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

104

110

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“…Manipulation of virtually all components of the Drosophila insulin signaling pathway has been shown to alter organ and body size as a result of cell autonomous changes in cell size and number (reviewed in Stocker and Hafen, 2000;Weinkove and Leevers, 2000;Oldham and Hafen, 2003). For example, inactivation of positively acting molecules such as the insulin receptor, PI3K, chico (the insulin receptor substrate (IRS) ortholog), PDK1, Akt, TOR, Rheb, or S6K decreases organ and cell size concomitant with a slowing down of the cell cycle, while overexpression of many of these molecules increases organ and cell size (Bohni et al, 1999;Chen et al, 1996;Leevers et al, 1996;Montagne et al, 1999;Verdu et al, 1999;Oldham et al, 2000;Zhang et al, 2000;Rintelen et al, 2001;Saucedo et al, 2003;Stocker et al, 2003). Consistently, inactivation of negatively acting molecules such as PTEN or TSC1/2 increases organ and cell size, while their overexpression decreases organ and cell size (Gao et al, 2000;Goberdhan et al, 1999;Huang et al, 1999;Gao and Pan, 2001;Tapon et al, 2001a;Potter et al, 2002).…”

Section: Rheb An Activator Of Tor That Is Inhibited By Tsc2mentioning

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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“…In general, inactivation of genes that promote the insulin/PI3K/TOR pathway including Inr, IRS1-2/ Chico, PI3K/Dp110, PDK1, Akt, TOR, and S6K, reduces cell, organ or organism size; whereas activation of several of these genes has the opposite effect [86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102]. Conversely, mutations in negative regulators of the pathway, such as PTEN, TSC1 or TSC2, increase cell or organ size; whereas overexpression of PTEN or both TSC1 and TSC2 causes reduced cell size or organ size ( Figure 2) [76,[103][104][105][106][107][108].…”

Section: Insulin/pi3-kinase/tor Pathwaymentioning

confidence: 99%

Molecular mechanism of size control in development and human diseases

Yang

2011

Cell Res

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How multicellular organisms control their size is a fundamental question that fascinated generations of biologists. In the past 10 years, tremendous progress has been made toward our understanding of the molecular mechanism underlying size control. Original studies from Drosophila showed that in addition to extrinsic nutritional and hormonal cues, intrinsic mechanisms also play important roles in the control of organ size during development. Several novel signaling pathways such as insulin and Hippo-LATS signaling pathways have been identified that control organ size by regulating cell size and/or cell number through modulation of cell growth, cell division, and cell death. Later studies using mammalian cell and mouse models also demonstrated that the signaling pathways identified in flies are also conserved in mammals. Significantly, recent studies showed that dysregulation of size control plays important roles in the development of many human diseases such as cancer, diabetes, and hypertrophy.

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PDK1 regulates growth through Akt and S6K in Drosophila

Cited by 158 publications

References 41 publications

DysregulatedTCL1promotes multiple classes of mature B cell lymphoma

DysregulatedTCL1promotes multiple classes of mature B cell lymphoma

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

Molecular mechanism of size control in development and human diseases

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