The TCL1 oncoprotein binds the RNase PH domains of the PNPase exoribonuclease without affecting its RNA degrading activity

French, Samuel W.; Dawson, David W.; Chen, Hsiao‐Wen; Rainey, Robert N.; Sievers, Stuart A.; Balatoni, Cynthia E.; Wong, Larry; Troke, Joshua J.; Nguyen, Mai; Koehler, Carla M.; Teitell, Michael A.

doi:10.1016/j.canlet.2006.07.006

Cited by 23 publications

(31 citation statements)

References 55 publications

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“…Table S1 lists the top eight hits found in Tcl1 protein complexes but not in Dleu7 complexes. Interestingly, Pnpt1, a previously reported Tcl1 interactor (13), was most abundant in Tcl1 protein complexes (Table S1). We focused our attention on Dnmt3A and Dnmt3B, because aberrant DNA methylation has been hypothesized to contribute to cancer development, and inactivating mutations of DNMT3A were recently reported in AML and MDS (10)(11)(12).…”

Section: Resultsmentioning

confidence: 69%

Tcl1 protein functions as an inhibitor of de novo DNA methylation in B-cell chronic lymphocytic leukemia (CLL)

Palamarchuk

Yan

Zanesi

et al. 2012

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

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B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia. Deregulation of the T-cell leukemia/lymphoma 1 oncogene (TCL1) in mouse B cells causes a CD5 + leukemia similar to aggressive human CLL. To examine the mechanisms by which Tcl1 protein exerts its oncogenic activity in B cells, we performed proteomics experiments to identify its interacting partners. We found that Tcl1 physically interacts with de novo DNA methylthansferases Dnmt3A and Dnmt3B. We further investigated the effects of Tcl1 up-regulation on the enzymatic activity of Dnmt3A and found that Tcl1 overexpression drastically inhibits Dnmt3A function. In addition, B cells from TCL1 transgenic mice showed a significant decrease in DNA methylation compared with WT controls. Similarly, CLL samples with high Tcl1 expression showed a decrease in DNA methylation compared with CLL samples with low Tcl1 expression. Given the previous reports of inactivating mutations of DNMT3A in acute myelogenous leukemia and myelodysplastic syndrome, our results suggest that inhibition of de novo DNA methylation may be a common oncogenic mechanism in leukemogenesis.T he lymphocytes of B-cell chronic lymphocytic leukemia (CLL) are mostly resting cells with mature appearance and the B220 + CD5 + phenotype (1, 2). The TCL1 oncogene has been identified as a target of chromosomal translocations and inversions at 14q31.2 in T-cell prolymphocytic leukemias (3). We previously showed that transgenic mice overexpressing TCL1 in B cells develop an aggressive form of CLL (4), and that aggressive human CLLs overexpress Tcl1 (5). These findings indicate that deregulation of TCL1 is critically important in the pathogenesis of the aggressive form of CLL. In previously work, we demonstrated that Tcl1 is a coactivator of the Akt oncoprotein (6). Akt could be robustly activated in mouse B cells by homozygous deletion of Pten (7). Surprisingly, these mice did not develop B-cell malignancies (7), suggesting that Tcl1 deregulation in B cells causes CLL by mechanisms other than Akt activation. We recently reported that Tcl1 functions as a transcriptional regulator and contributes to CLL pathogenesis by inhibiting activating protein 1 (AP-1) and activating NF-κB, and that that CLL-specific TCL1 mutants show gain of function in AP-1 inhibition (8).Three human genes-DNMT1, DNMT3A, and DNMT3B-encode DNA methyltransferases, enzymes responsible for methylation of CpG islands (9). Whereas DNMT1 functions mainly in maintaining methylation patterns, DNMT3A and DNMT3B encode de novo DNA methyltransferases (9). Inactivating mutations of DNMT3A have been reported in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) (10-12). To further examine the mechanisms by which Tcl1 protein exerts oncogenic activity in B-cells, we used a proteomic approach to identify its interacting partners. This approach identified Dnmt3a and Dnmt3b as putative Tcl1 interactors.

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Section: Resultsmentioning

confidence: 69%

Tcl1 protein functions as an inhibitor of de novo DNA methylation in B-cell chronic lymphocytic leukemia (CLL)

Palamarchuk

Yan

Zanesi

et al. 2012

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

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“…In addition, the present finding that TCL1 enters one-cell embryo pronuclei, while phosphorylated AKT does not, suggests that TCL1 also plays an AKTindependent role(s) at the beginning of embryo development. In light of the recent finding that TCL1 binds the PNPase exoribonuclease, an enzyme that specifically degrades poly-A þ RNAs, 12 it is tempting to hypothesize that this factor is also relevant for the degradation of maternally derived messages.…”

Section: P-ser473mentioning

confidence: 99%

TCL1 promotes blastomere proliferation through nuclear transfer, but not direct phosphorylation, of AKT/PKB in early mouse embryos

et al. 2007

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The T-cell leukemia/lymphoma 1 (TCL1) gene is expressed during T-cell and B-cell development and involved in the pathogenesis of T-cell and B-cell leukemias/ lymphomas. It also plays a key regulatory role in the maintenance of the proliferation versus differentiation balance of embryonic stem (ES) cells. We previously characterized the expression of TCL1 during preimplantation embryo development, namely in the cells from which ES cells are derived, and found that it shuttles between blastomere cortical regions and the nucleus by a cell cycle-dependent fashion and to be required for early blastomere proliferation, but not the acquisition of first embryonal differentiation traits. TCL1 promotes cell proliferation by heterodimerization with AKT/PKB, a serine/threonine kinase having a central role in the signaling pathways controlling cell proliferation and survival. We have now analyzed TCL1/AKT interaction in the preimplantation mouse embryo and found that TCL1 is not relevant to AKT phosphorylation in one-cell and two-cell embryos. Therefore, early mouse embryos display a physiological dissociation between the TCL1 functions of AKT phosphorylation and phosphorylated AKT transfer to nucleus, pinpointing the latter function as the essential one for the AKT-mediated promotion of cell proliferation. We also provide evidence that TCL1 enters one-cell embryo pronuclei, while phosphorylated AKT does not, suggesting that TCL1 also plays an AKT independent role(s) at the beginning of embryo development

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“…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 . More recently, TCL1 has been shown to also bind another type of PH domain (of the PNPase exoribonuclease) (French et al, 2006). Furthermore, the study of Tcl1 in murine systems has shown that Tcl1 is expressed in the ovary, testis and preimplantation embryos (Hallas et al, 1999;Narducci et al, 1997aNarducci et al, , b, 2002 and in murine embryonic stem (ES) cells (Ivanova et al, 2006).…”

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 TCL1 oncoprotein binds the RNase PH domains of the PNPase exoribonuclease without affecting its RNA degrading activity

Cited by 23 publications

References 55 publications

Tcl1 protein functions as an inhibitor of de novo DNA methylation in B-cell chronic lymphocytic leukemia (CLL)

Tcl1 protein functions as an inhibitor of de novo DNA methylation in B-cell chronic lymphocytic leukemia (CLL)

TCL1 promotes blastomere proliferation through nuclear transfer, but not direct phosphorylation, of AKT/PKB in early mouse embryos

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

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