The Protooncogene TCL1 Is an Akt Kinase Coactivator

Laine, Jarmo; Künstle, Gerald; Obata, Toshiyuki; Ma, Sha; Noguchi, Masayuki

doi:10.1016/s1097-2765(00)00039-3

Cited by 312 publications

(334 citation statements)

References 46 publications

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“…27,28 This finding is concordant with a recent report indicating that Tcl1 overexpression in a human cell line markedly enhances cell survival following treatment with the apoptosis-inducing agents, anti-CD3, anti-Fas, and dexamethasone. 17 It is not clear why the single-positive thymocytes that do not express Tcl1 at easily detectable levels were hypersensitive to CD3 ligation in Tcl1 Ϫ/Ϫ mice. It is possible that undetectable levels of Tcl1 expression in a subpopulation of the thymic CD4 cells may have a role in their survival.…”

Section: Discussionmentioning

confidence: 99%

“…Since earlier studies suggest roles for the human TCL1 gene product in cellular proliferation 7,8 and in antiapoptotic signaling, 10,16,17 we tested the effects of apoptotic and proliferative stimuli under in vivo and in vitro conditions. When the rate of spontaneous apoptosis was assessed by measuring cell viability in thymocytes cultured in media or for thymocytes stimulated with dexamethasone, significant differences were not observed for the wild-type and null mice (data not shown).…”

Section: Hypersensitivity Of Tcr-bearing Thymocytes To Cd3 Ligation Inmentioning

confidence: 99%

“…14,15 In the Akt signaling cascade, Tcl1 acts as an Akt cofactor to enhance kinase activity and nuclear translocation. 16,17 Tcl1 binding to Akt also facilitates the formation of Akt-Tcl1 hetero-oligomers. 18 The resultant (trans)phosphorylation of Akt1 at Ser473 may thus amplify the phosphatidylinositol 3 (PI3)-Akt1 pathway to contribute a survival advantage.…”

Section: Introductionmentioning

confidence: 99%

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Impaired T- and B-cell development in Tcl1-deficient mice

Kang

Narducci

Lazzeri

et al. 2005

Blood

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IntroductionT-cell prolymphocytic leukemias (T-PLLs) in humans often have chromosomal translocations that juxtapose the T-cell receptor (TCR) ␣/␦ or ␤ locus to the proximity of the T-cell leukemia/ lymphoma-1 gene (TCL1) located in the 14q32.1 region or, less frequently, to lay near its mature T-cell proliferation 1 (MTCP1) gene homolog in the Xq23 region. [1][2][3][4] The ensuing aberrant influence of a TCR enhancer element results in overexpression of the TCL1 or MTCP1 genes. 5,6 Overexpression of either TCL1 or MTCP1 in transgenic mouse models employing a T-cell-specific promoter may also result in a T-cell leukemia that resembles human T-PLL. 7,8 In addition to the implicit TCL1 involvement in this T-cell malignancy, a variety of B-lineage tumor cell lines, ranging from pre-B cell to mature B-cell phenotype, have also been shown to express high Tcl1 levels. [9][10][11] Moreover, TCL1 overexpression under the control of B-lineage-specific enhancer and promoter elements has been shown to promote B-cell chronic lymphocytic leukemia 12 and B-cell lymphomas in mice. 13 An important clue to the role of TCL1 in the leukomogenesis process is provided by the functional linkage of Tcl1 to Akt kinase, an intracellular component that participates in the transduction of antiapoptotic and proliferative signals. 14,15 In the Akt signaling cascade, Tcl1 acts as an Akt cofactor to enhance kinase activity and nuclear translocation. 16,17 Tcl1 binding to Akt also facilitates the formation of Akt-Tcl1 hetero-oligomers. 18 The resultant (trans)phosphorylation of Akt1 at Ser473 may thus amplify the phosphatidylinositol 3 (PI3)-Akt1 pathway to contribute a survival advantage. 19 Normally, TCL1 expression is tightly regulated, being confined to lymphoid and germinal cells in humans and mice. In human B-lineage cells, TCL1 expression is initiated in pro-B cells, peaks in the pre-B cells, and persists in immunoglobulin M (IgM)-bearing B cells. 5 High expression levels of TCL1 transcripts have been found in the mantle zone B cells in the spleen, whereas TCL1 expression is down-regulated in germinal center and marginal zone B cells, and is extinguished in terminally differentiated plasma cells. [9][10][11] In human T-lineage cells, TCL1 expression is seen in the intrathymic CD4 Ϫ CD8 Ϫ subpopulation, but not in mature T cells. In the present study, we observed a similar pattern for Tcl1 expression in mouse T-and B-lineage cells. In order to gain insight into the physiologic role(s) that Tcl1 may have in T and B lymphopoiesis, we have examined both pathways of lymphocyte development and their cooperative function in antibody responses of Tcl1-deficient mice. These mice are shown to have modestly compromised T and B lymphopoiesis due either to impaired cellular proliferation or enhanced apoptosis. Materials and methodsMice, cell preparation, cell counting, and statistical analysis Tcl1 Ϫ/Ϫ and Tcl1 ϩ/Ϫ mice were generated as described previously. 20 Bone marrow (BM) cells were obtained by flushing the cavities of both femoral and tibial ...

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Section: Discussionmentioning

confidence: 99%

Section: Hypersensitivity Of Tcr-bearing Thymocytes To Cd3 Ligation Inmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Impaired T- and B-cell development in Tcl1-deficient mice

Kang

Narducci

Lazzeri

et al. 2005

Blood

View full text Add to dashboard Cite

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“…14 TCL1 functions as a co-activator of the prosurvival serine threonine kinase AKT (PKB) by interacting with its pleckstrin homology domain. 15,16 Besides acting as a positive modulator of AKT kinase activity, TCL1 also enhances NF-kB activity and inhibits activator protein 1 (AP-1) transcription factor activity. 17 In CLL, TCL1 is differentially expressed, and higher TCL1 protein levels correlate with more aggressive clinical features.…”

Section: Introductionmentioning

confidence: 99%

Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia

et al. 2012

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The tissue microenvironment in chronic lymphocytic leukemia (CLL) has an increasingly recognized role in disease progression, but the molecular mechanisms of cross talk between CLL cells and their microenvironment remain incompletely defined. Bone marrow stromal cells (BMSC) protect CLL cells from apoptosis in a contact-dependent fashion, and have been used for the identification of key pathways such as the CXCR4 --CXCL12 axis. To further dissect the molecular impact of BMSC on survival and the molecular activation signature of CLL cells, we co-cultured CLL cells with different BMSC. Gene expression profiling of CLL cells revealed that the lymphoid proto-oncogene TCL1 was among the top genes upregulated in CLL cells by BMSC. TCL1 mRNA and protein upregulation by BMSC was paralleled by decreases of TCL1-interacting FOS/JUN, and confirmed by qRT-PCR, immunoblotting, immunoprecipitations, and flow cytometry. Stroma mediated increases in TCL1 were also associated with decreased levels of TCL1-regulatory micro-RNAs (miR-29b, miR-181b, miR-34b). These findings demonstrate that the microenvironment has a proactive role in the regulation of the known signaling enhancer and pro-survival molecule TCL1 in CLL. This provides a further rationale for therapeutically targeting the cross talk between CLL and BMSC.

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“…Moreover, TCL1 has been shown to be constitutively expressed in a tightly regulated manner in lymphoid cells of B and T origins (Narducci et al, 1997a, b;Takizawa et al, 1998;Teitell et al, 1999;Kang et al, 2005). Functionally, Tcl1 exerts its function by binding the pleckstrin domain of AKT proteins, thereafter increasing AKT kinase activity and enhancing AKT nuclear translocation in vitro (Laine et al, 2000;Pekarsky et al, 2000;Kunstle et al, 2002) and in vivo (Zanesi et al, 2006). In particular, the presence of Tcl1 allows the serine-473 transphosphorylation of AKT proteins in the oligomeric complex, thus ensuring maximal kinase activity and facilitating an amplification loop of the antiapoptotic, proliferative stimuli controlled by the PI3-kinase-AKT pathway .…”

Section: Introductionmentioning

confidence: 99%

The Tcl1 oncogene defines secondary hair germ cells differentiation at catagen–telogen transition and affects stem-cell marker CD34 expression

et al. 2009

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Overexpression of the TCL1 gene family plays a role in the onset of T-cell leukemias in mice and in humans. The Tcl1 gene is tightly regulated during early embryogenesis in which it participates in embryonic stem (ES)-cells proliferation and during lymphoid differentiation. Here, we provide evidences that Tcl1 is also important in mouse hair follicle (HF) and skin homeostasis. We found that Tcl1 À/À adult mice exhibit hair loss, leading to alopecia with extensive skin lesions. By analysing Tcl1 expression in the wild-type (wt) skin through different stages of hair differentiation, we observe high levels in the secondary hair germ (HG) cells and hair bulges, during early anagen and catagen-telogen transition phases. The loss of Tcl1 does not result in apparent skin morphological defects during embryonic development and at birth, but its absence causes a reduction of proliferation in anagen HFs. Importantly, we show the that absence of Tcl1 induces a significant loss of the stem-cell marker CD34 (but not a6-integrin) expression in the bulge cells, which is necessary to maintain stem-cell characteristics. Therefore, our findings indicate that Tcl1 gene(s) might have important roles in hair formation, by its involvement in cycling and self-renewal of transient amplifying (TA) and stem-cell (SC) populations.

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The Protooncogene TCL1 Is an Akt Kinase Coactivator

Cited by 312 publications

References 46 publications

Impaired T- and B-cell development in Tcl1-deficient mice

Impaired T- and B-cell development in Tcl1-deficient mice

Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia

The Tcl1 oncogene defines secondary hair germ cells differentiation at catagen–telogen transition and affects stem-cell marker CD34 expression

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