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[Cancer Research 65, 4515-4519, June 1, 2005]
© 2005 American Association for Cancer Research

Priority Reports

Akt Phosphorylates Tal1 Oncoprotein and Inhibits Its Repressor Activity

Alexey Palamarchuk, Alexey Efanov, Vadim Maximov, Rami I. Aqeilan, Carlo M. Croce and Yuri Pekarsky

Human Cancer Genetics Program, Comprehensive Cancer Center and Department of Molecular Virology, Immunology, and Medical Genetics, OSU School of Medicine, Ohio State University, Columbus, Ohio

Requests for reprints: Yuri Pekarsky, Comprehensive Cancer Center, Ohio State University, 435 Wiseman Hall, 410 West 12th Avenue, Columbus, OH 43210. Phone: 614-292-3120; Fax: 614-292-3312; E-mail: Pekarsky.Yuri{at}osumc.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The helix-loop-helix transcription factor Tal1 is required for blood cell development and its activation is a frequent event in T-cell acute lymphoblastic leukemia. The Akt (protein kinase B) kinase is a key player in transduction of antiapoptotic and proliferative signals in T cells. Because Tal1 has a putative Akt phosphorylation site at Thr90, we investigated whether Akt regulates Tal1. Our results show that Akt specifically phosphorylates Thr90 of the Tal1 protein within its transactivation domain in vitro and in vivo. Coimmunoprecipitation experiments showed the presence of Tal1 in Akt immune complexes, suggesting that Tal1 and Akt physically interact. We further showed that phosphorylation of Tal1 by Akt causes redistribution of Tal1 within the nucleus. Using luciferase assay, we showed that phosphorylation of Tal1 by Akt decreased repressor activity of Tal1 on EpB42 (P4.2) promoter. Thus, these data indicate that Akt interacts with Tal1 and regulates Tal1 by phosphorylation at Thr90 in a phosphatidylinositol 3-kinase–dependent manner.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Activation of TAL1 gene (also known as SCL or TCL5) by chromosomal translocations or deletions at 1p32 is a common event in T-cell acute lymphoblastic leukemia (1). Tal1, absent in normal T cells, is expressed in the majority of T-cell acute lymphoblastic leukemia (1). Transgenic expression of Tal1 in T cells results in the development of clonal T-cell leukemias and lymphomas (2, 3). The TAL1 gene encodes a helix-loop-helix transcription factor (1). These factors often form homodimeric and heterodimeric complexes that recognize specific DNA sequences (1). Although Tal1 cannot form homodimers, it interacts with other helix-loop-helix factors such as E47 and HEB (1). A recent report showed that Tal1 induces T-cell acute lymphoblastic leukemia primarily by repressing transcriptional activity of E47 (3). Tal1 gene knockout in mice resulted in midgestational lethality and complete absence of yolk sac erythropoiesis (4). Further analysis of chimeric animals showed that Tal1 is essential for development of all hematopoietic lineages (4). Similarly to other helix-loop-helix factors, the activity of Tal1 is regulated in part by phosphorylation. Two phosphorylation sites have been reported to date. Phosphorylation of Ser122 by the mitogen-activated protein kinase extracellular signal-regulated kinase-1 was found to increase the activity of a transcriptional activation domain (5, 6). Another serine residue, Ser172, located near the DNA binding domain, can be phosphorylated by cyclic AMP–dependent protein kinase (7). This phosphorylation was found to affect the DNA binding activity of Tal1 (7). The protein kinase Akt (protein kinase B) is an important molecule in transduction of antiapoptotic and proliferative signals in T cells (8). Its activation by various growth and survival factors involves a phosphatidylinositol 3-kinase (PI-3K)–dependent membrane translocation and the phosphorylation of Thr308 and Ser473 mediated by PDK1 (9, 10). A number of studies showed that Akt regulates a variety of critical targets involved in cell survival like Bad, Raf, and IKK{alpha} (8, 11, 12). Previously, we and others reported that Akt interacts with the Tcl1 oncoprotein, resulting in increased Akt kinase activity and nuclear translocation (13, 14). We also showed that Akt phosphorylates and regulates Nur77, a transcription factor regulating proapoptotic genes in T cells (15). To further characterize the role of Akt pathway in lymphoid cells, we identified lymphoid-related nuclear targets of Akt relevant to these cells. Because the residues surrounding Thr90 of Tal1 (RHRVPT) resemble the Akt phosphorylation site (RXRXXS/T; ref. 9), we considered Tal1 a good candidate target. Thus, we investigated the possible phosphorylation of Tal1 by Akt.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
DNA constructs and transfection, immunoprecipitation, Western blotting, and immunofluorescence. Full-length TAL1, TCL1, and FHIT cDNAs were cloned into a pCMV-HA vector (Clontech, Palo Alto, CA) using standard protocols. An additional HA tag was added in the 3' terminus of all three open reading frames. TAL1(T90A)-HA and TAL1(T90D)-HA constructs were created using standard PCR-based mutagenesis. Full-length E47 cDNA was cloned into a pCDNA4-HisMaxA vector (Omni-E47, Invitrogen, Carlsbad, CA). Full-length DEDD cDNA was cloned into a pEGFP-N1 vector (Clontech). The AKT-HA construct was previously described (13). Myc-AKT1 construct was purchased from Upstate Biotechnology (Lake Placid, NY). 293 and NIH-3T3 cells were grown in RPMI 1640 with 10% fetal bovine serum (FBS). Transfections, except luciferase assay experiments (see below), cell lysate preparations, immunoprecipitations, and Western blot analysis were carried out as previously described (13). 293 cells were starved overnight in RPMI and 0% FBS, and the cells were treated with insulin (5 µg/mL) for 30 minutes or with Wortmannin (200 nmol/L) for 30 minutes followed by insulin for 30 minutes and lysed (see Fig. 2A and B). Antibodies used were anti-HA, clone 11, monoclonal anti–glutathione S-transferase (GST; BabCO, Richmond, CA), anti-Akt, anti–phospho-Ser473-Akt, polyclonal anti–phospho-Akt substrate (Cell Signalling Technology, Beverly, MA), and anti-Myc clone 9E10 (Zymed laboratories, South San Francisco, CA). Phospho-Tal1 antibody was custom-made by Zymed laboratories. Antibody was raised against peptide EARHRVP-pT-TEL and absorbed against the unphosphorylated peptide. Immunofluorescence was carried out as previously described using Zeiss LCM 510 confocal microscope (13).



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  		Figure 2. Akt phosphorylates Tal1 in a PI-3K–dependent manner. A, 293 cells were transfected with TAL1. Lane 1, cells were grown under normal conditions (10% FBS in RPMI). Cells were starved overnight in 0% FBS (lanes 2-4), untreated (lane 2), treated with insulin (5 µg/mL) for 30 minutes (lane 3), or treated with Wortmannin (200 nm) for 30 minutes followed by treatment with insulin (5 µg/mL) for 30 minutes (lane 4). Lysates were immunoblotted with anti–phospho-Akt substrate (top), anti-HA (top middle), anti–phospho-Akt (S473; bottom middle), or anti-Akt (bottom) antibodies. B, 293 cells were cotransfected with TAL1-HA and TCL1-HA (lanes 1 and 3) or with TAL1-HA and FHIT-HA (lanes 2 and 4). Cells were starved overnight in 0% FBS (lanes 2-4), untreated (lanes 1 and 2), and treated with insulin (5 µg/mL) for 30 minutes (lanes 3 and 4). Lysates were immunoblotted with anti–phospho-Akt substrate (top) and anti-HA (middle and bottom) antibodies. C, 293 cells were cotransfected with TAL1-HA and AKT-Myc (lanes 1-4) or with TAL1(T90A)-HA and AKT-Myc (lanes 5-8). A total of 107 cells were used in each experiment. One third of the total cell lysate was used for each immunoprecipitation. Half of each immunoprecipitation reaction was loaded on each lane. After lysis, immunoprecipitations were carried out using anti-Myc antibody (lanes 2 and 5), mouse immunoglobulin G (lanes 3 and 6), or anti-HA antibody (lanes 4 and 7). Western blotting was carried out as indicated. Lanes 1 and 8, lysates were loaded to check expression levels of AKT-Myc (top) or TAL1-HA and TAL1(T90A)-HA (bottom).

 
In vitro phosphorylation. The DNA segment encoding part of Tal1 transactivating domain (amino acids 46-145) was cloned into a pGEX-4T-1 vector (Pharmacia, Piscataway, NJ). The GST fusion protein was isolated according to the recommendations of the manufacturer. Activated Akt was purchased from Upstate Biotechnology. In vitro phosphorylation was carried out using an Akt kinase assay kit (Cell Signalling Technology) with the following modifications: 200 ng of activated Akt and 500 ng of GST fusion proteins were used in each reaction. Western blot detection was carried out using polyclonal anti–phospho-Akt substrate antibody (Cell Signalling Technology).

Luciferase assay. The initial 675 bp of murine Epb42 (P4.2) promoter (16) was cloned into a pGL3 vector (Promega, Madison, WI). 293 cells were transfected with constructs indicated in Fig. 4. Firefly and renilla luciferase activities were assayed with the dual luciferase assay system (Promega) and firefly luciferase activity was normalized with respect to renilla luciferase activity. All experiments were carried out in duplicate and repeated three times with consistent results.



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  		Figure 4. Phosphorylation of T90 inhibits repressor activity of Tal1. 293 cells were transfected with 0.5 µg of reporter construct, and 50 ng pRL-TK and 250 ng Omni-E47 (where indicated) constructs. Black columns, 250 ng of TAL1 constructs were used; light gray columns, 125 ng of TAL1 constructs were used; dark gray columns, 62.5 ng of TAL1 constructs were used. The activity of the basal promoter in 293 cells was set as 1. Firefly and renilla luciferase activities were assayed with the dual luciferase assay system (Promega) and firefly luciferase activity was normalized with respect to renilla luciferase activity. Y axis, normalized luciferase numbers.

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Akt phosphorylates Tal1 in vitro and in vivo. Because Tal1 contains a putative Akt phosphorylation site, we investigated whether Tal1 is phosphorylated by Akt at Thr90. In in vitro phosphorylation experiments, we used a GST-linked part of Tal1 transactivation domain (amino acids 46-145) containing the putative Akt phosphorylation site (RHRVPT). Figure 1A shows that Akt specifically phosphorylates Thr90 in the Tal1 transactivation domain in a time-dependent manner (lanes 2-4), but not GST alone (lane 5).



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  		Figure 1. Akt phosphorylates Tal1 in vitro and in vivo. A, GST-fusion proteins, 0.5 µg, were incubated with 200 ng of activated Akt and immunoblotted with anti–phospho-Akt substrate antibody (top) or with anti-Akt and anti-GST antibodies (bottom). Phosphorylation was carried out for 0 minutes (lane 1), 5 minutes (lane 2), 10 minutes (lane 3), and 20 minutes (lanes 4 and 5). Lanes 1-4, GST-Tal1 fusion protein was used in the reaction. Lane 5, GST alone was used. B, 293 cells were cotransfected with TAL1-HA and kinase-inactive AKT-HA K179M (lane 1), Tal1 and AKT-HA (lane 2), and with AKT-HA only (lane 3). Lysates were immunoblotted with anti–phospho-Akt substrate (top), anti-HA (middle), or antitubulin (bottom) antibodies. C, 293 cells were cotransfected with wt-TAL1-HA (lane 1) or with TAL1(T90A)-HA mutant (lane 2). Western blot analysis was carried out as in B.

 
Because Akt phosphorylates Tal1 in vitro, we proceeded to determine if this phosphorylation occurs also in vivo. We transfected 293 cells with TAL-HA and kinase-inactive AKT (containing K179M inactivating mutation) or wild-type (wt) AKT. The expression of Tal1 was detected using anti-HA antibody and the amount of phospho-Tal1 was detected using anti–phospho-Akt substrate antibody (Fig. 1B). In the presence of overexpressed Akt, the amount of phosphorylated Tal1 increased severalfold (Fig. 1B, lane 2 versus lane 1) whereas no signal was detected in the absence of Tal1 expression (Fig. 1B, lane 3); the signal on Fig. 1B (lane 1) represents phosphorylation of Tal1 by endogenous Akt. To prove that Akt indeed phosphorylates Thr90 of Tal1, we transfected wtTAL1-HA or mutant TAL1(T90A)-HA constructs into 293 cells. As expected, no phosphorylation signal was detected in the cells expressing T90A TAL1 mutant (Fig. 1C, lane 2 versus lane 1). This suggests that Akt phosphorylates Thr90 of Tal1 in vivo.

The activation of Akt by insulin and various survival and growth factors, such as insulin and platelet-derived growth factor, involves a PI-3K–dependent membrane translocation and a phosphorylation of Thr308 and Ser473 of Akt mediated by PDK-1 (9, 10). Wortmannin, a PI-3K inhibitor, inhibits this activation of Akt (17). The activation of Akt by treatment of 293 cells with insulin is a model system often used to assay phosphorylation of various Akt targets (9). Thus, we proceeded to determine whether Akt phosphorylates Tal1 in a PI-3K–dependent manner. 293 cells were transfected with TAL1-HA and starved overnight in 0% FBS. Cells were then treated with insulin or Wortmannin and insulin, and the amount of phosphorylated Tal1 was detected with anti–phospho-Akt substrate antibody. Figure 2A (top) shows that insulin treatment significantly increases the phosphorylation of Tal1 by endogenous Akt and that treatment with Wortmannin completely inhibits this effect. As expected, Akt was activated (i.e., phosphorylated at Ser473) by insulin and this effect was inhibited by Wortmannin (Fig. 2A, lanes 2-4). Thus, Tal1 is phosphorylated by endogenous Akt in 293 cells at Thr90 in a PI-3K–dependent manner.

We and others previously reported that Tcl1 oncoprotein functions as coactivator of Akt (13, 14). Because Tcl1, Tal1, and Akt function as oncogenes in T cells and because Tcl1 activates Akt, it is possible that Tcl1 expression would increase the phosphorylation of Tal1 by Akt. Figure 2B shows that this is indeed the case. 293 cells were cotransfected with TAL1-HA and TCL1-HA or FHIT-HA (as a negative control). In starved cells Tcl1 expression resulted in the increase of phosphorylation level of Tal1 (Fig. 2B, lane 1 versus lane 2), although this effect was no longer apparent after stimulation with insulin (Fig. 2B, lanes 3 and 4).

Tal1 physically interacts with Akt. Because Akt phosphorylates Tal1 in vitro and in vivo, it is likely that these two proteins physically interact. To prove this interaction, we cotransfected 293 cells with AKT-Myc and TAL1-HA or TAL1(T90A)-HA and carried out coimmunoprecipitation experiments using anti-HA and anti-Myc antibodies. Figure 2C (lane 2, bottom) shows detection of Tal1 in Akt immune complexes precipitated with the anti-Myc antibody. In the reverse immunoprecipitation experiment, Akt coimmunoprecipitated with Tal1 as shown by Western blotting with an anti-Myc antibody (Fig. 2C, lane 4, top), proving that Tal1 does indeed physically interact with Akt. Similarly, mutant Tal1(T90A) was coimmunoprecipitated with Akt (Fig. 2C, lanes 5 and 7).

Phosphorylation of Thr90 causes redistribution of Tal1 within the nucleus. The intracellular localization of Tal1 is mostly nuclear (1). Akt, on the other hand, is primarily localized in the cytoplasm but some nuclear presence was also observed (17). It was also reported that in insulin-stimulated 293 cells, activated Akt can translocate to the nucleus (18). We previously reported that Tcl1 oncoprotein can also be involved in the nuclear translocation of Akt (13). Therefore, most likely, Akt phosphorylates Tal1 in the nucleus. To investigate whether the phosphorylation at Thr90 of Tal1 affects its intracellular localization, we transfected NIH-3T3 cells with TAL1-HA and studied the location of Tal1 and phospho-Tal1 by immunofluorescence. As expected, Tal1 showed clear nuclear localization with slightly uneven distribution within the nucleus in almost 100% of cells (Fig. 3, top). Interestingly, in most of the cells, phospho-Tal1 showed significantly different nuclear staining: it localized only in several distinct globular compartments within the nucleus resembling nucleoli. To determine whether phospho-Tal1 indeed localizes in nucleoli, we used the DEDD-GFP construct. DEDD is a death effector domain–containing protein involved in the induction of apoptosis within the nucleus previously reported to localize in the nucleoli (19). Figure 3 (bottom) shows that phospho-Tal1 and DEDD are colocalized within the nucleus when cotransfected into NIH-3T3 cells, suggesting that phospho-Tal1 is localized in the nucleoli.



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  		Figure 3. Phosphorylation of T90 causes nuclear redistribution of Tal1. Top, NIH-3T3 cells were transfected with TAL1-HA, immunostained with anti-HA (red) or with anti–phospho-(T90)-Tal1 antibody (green), and visualized using confocal microscopy. Light microscopy view is also shown (right). Bottom, NIH-3T3 cells were cotransfected with TAL1-HA and DEDD-GFP, immunostained with anti–phospho-(T90)-Tal1 antibody (red), and visualized as above.

 
Akt inhibits the repressor transcriptional activity of Tal1. As mentioned above, Tal1 acts as transcriptional repressor. It was recently shown that Tal1 induces T-cell acute lymphoblastic leukemia by repressing transcriptional activity of E47 (3). E47 protein is encoded by the E2A gene which plays a critical role in the regulation of early B-cell differentiation (1). E47 and Tal1 are parts of a larger complex that also contains GATA-1, LMO2, and Ldb1 (16). This complex regulates transcription of EPB42 (P4.2) gene, an important component of red cell membrane skeleton (16). The P4.2 promoter contains 2 E boxes, binding sites for E47/Tal1 complex (16). To investigate whether phosphorylation of Tal1 by Akt would affect the transcriptional activity of Tal1, we cloned the last 675 bp of murine P4.2 promoter into a pGL3 vector containing the luciferase reporter gene and carried out reporter gene assay experiments using this construct. In these assays, we used wtTAL1-HA, TAL1(T90A)-HA, and TAL1(T90D)-HA constructs. The latter construct was used to mimic the phosphorylated form of Tal1. 293 cells were cotransfected with the reporter construct Omni-E47 and with each of the three TAL1 constructs in three different concentrations (Fig. 4). As expected, E47 alone showed five to seven times activation of P4.2 promoter whereas in higher concentration, expression of wt Tal1 or Tal1(T90A) mutant completely inhibited this effect (black bars). Depending on the concentration, Tal1(T90D) mutant showed 40% to 100% greater transcriptional activity than wt Tal1 or Tal1(T90A), although in all concentrations the repressor activity of Tal1 was not completely eliminated (Fig. 4). These results suggest that the phosphorylation of Thr90 inhibits the function of Tal1 as a transcriptional repressor.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this report, we show that Tal1 is a novel target of Akt protein kinase. Our results show that Akt interacts with Tal1, phosphorylates Tal1 in vitro and in vivo in a PI-3K–dependent manner, causes redistribution of Tal1 within the nucleus, and inactivates Tal1 in its function as a transcriptional repressor. Because all previous data (including ours in Fig. 3) indicate that Tal1 is a nuclear protein and its cytoplasmic localization was never observed, the phosphorylation of Thr90 by Akt most likely takes place in the nucleus. Although Akt mostly localized in the cytoplasm, several reports showed that Akt can translocate in the nucleus, including data that in insulin-stimulated 293 cells activated Akt can translocate to the nucleus and our data showing that Tcl1 oncoprotein can translocate Akt to the nucleus (13, 17, 18). Because Tcl1 can cause translocation of Akt to the nucleus, our data in Fig. 2B showing that Tcl1 expression increases Tal1 phosphorylation in starved cells also support the hypothesis that Akt phosphorylates Tal1 in the nucleus. It is interesting that this effect of Tcl1 expression was only observed in starved cells. This suggests that the activation of Akt with an excess of growth and survival factors is superior and more powerful than the effect of Tcl1 expression. On the other hand, in hematopoietic tissues, such as spleen and lymph nodes, these external signals may be present at low levels if at all. We also previously reported that the activity of Akt in mouse thymus is extremely low (13). Therefore, under these conditions this effect of increased phosphorylation of Thr90 by Tcl1 expression might be very important.

Although the T90D mutant causes significant loss of function of Tal1 as an E47 inhibitor, this mutant still inhibits E47-dependent transcription two to three times. It is possible that in endogenous conditions this effect might be stronger and that other cofactors, such as GATA-1, LMO2, and Ldb1, might have an effect. On the other hand, the phosphorylation of Thr90 may make a difference between no transcription and decreased but still sufficient transcription.

Redistribution of phospho-Tal1 within the nucleus provides several possibilities for further investigations. It is not clear whether Tal1 has a specific function in the nucleoli; perhaps the possibility that this localization might have an effect on transcription of P4.2 or other genes should be investigated. Recent reports indicated that nucleolus plays an important role not only in ribosome biogenesis but also in cell proliferation and death (reviewed in ref. 20). Accumulation of apoptosis-related proteins in the nucleolar components suggests their function in the execution of cell death (20). It is possible therefore to speculate the role of phospho-Tal1 in these processes. On the other hand, phosphorylation of Thr90 might just exclude some Tal1 functions in other parts of the nucleus.


   Acknowledgments
 
Grant support: NIH grant CA76259 to C.M. Croce and Y. Pekarsky.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/ 3/05. Revised 3/28/05. Accepted 4/ 7/05.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Begley CG, Green AR. The SCL gene: from case report to critical hematopoietic regulator. Blood 1999;93:2760–70.[Free Full Text]
  2. O'Neil J, Billa M, Oikemus S, Kelliher M. The DNA binding activity of TAL-1 is not required to induce leukemia/lymphoma in mice. Oncogene 2001;20:3897–905.[CrossRef][Medline]
  3. O'Neil J, Shank J, Cusson N, Murre C, Kelliher M. TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB. Cancer Cell 2004;5:587–96.[CrossRef][Medline]
  4. Porcher C, Swat W, Rockwell K, Fujiwara Y, Alt FW, Orkin SH. The T cell leukemia oncoprotein SCL/tal-1 is essential for development of all hematopoietic lineages. Cell 1996;86:47–57.[CrossRef][Medline]
  5. Wadman IA, Hsu HL, Cobb MH, Baer R. The MAP kinase phosphorylation site of TAL1 occurs within a transcriptional activation domain. Oncogene 1994;9:3713–6.[Medline]
  6. Tang T, Prasad KS, Koury MJ, Brandt SJ. Mitogen-activated protein kinase mediates erythropoietin-induced phosphorylation of the TAL1/SCL transcription factor in murine proerythroblasts. Biochem J 1999;343 Pt 3:615–20.
  7. Prasad KS, Brandt SJ. Target-dependent effect of phosphorylation on the DNA binding activity of the TAL1/SCL oncoprotein. J Biol Chem 1997;272:11457–62.[Abstract/Free Full Text]
  8. Mok CL, Gil-Gomez G, Williams O, et al. Bad can act as a key regulator of T cell apoptosis and T cell development. J Exp Med 1999;189:575–86.[Abstract/Free Full Text]
  9. Chan TO, Rittenhouse SE, Tsichlis PN. AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem 1999;68:965–1014.[CrossRef][Medline]
  10. Bellacosa A, Chan TO, Ahmed NN, et al. Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene 1998;17:313–25.[CrossRef][Medline]
  11. Zimmermann S, Moelling K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science 1999;286:1741–4.[Abstract/Free Full Text]
  12. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 1999;401:82–5.[CrossRef][Medline]
  13. Pekarsky Y, Koval A, Hallas C, et al. Tcl1 enhances Akt kinase activity and mediates its nuclear translocation. Proc Natl Acad Sci U S A 2000;97:3028–33.[Abstract/Free Full Text]
  14. Laine J, Kunstle G, Obata T, Sha M, Noguchi M. The proto-oncogene TCL1 is an Akt kinase coactivator. Mol Cell 2000;6:395–407.[CrossRef][Medline]
  15. Pekarsky Y, Hallas C, Palamarchuk A, et al. Akt phosphorylates and regulates the orphan nuclear receptor Nur77. Proc Natl Acad Sci U S A 2001;98:3690–4.[Abstract/Free Full Text]
  16. Xu Z, Huang S, Chang LS, Agulnick AD, Brandt SJ. Identification of a TAL1 target gene reveals a positive role for the LIM domain-binding protein Ldb1 in erythroid gene expression and differentiation. Mol Cell Biol 2003;23:7585–99.[Abstract/Free Full Text]
  17. Ahmed NN, Franke TF, Bellacosa A, et al. The proteins encoded by c-akt and v-akt differ in post-translational modification, subcellular localization and oncogenic potential. Oncogene 1993;8:1957–63.[Medline]
  18. Andjelkovic M, Alessi DR, Meier R, et al. Role of translocation in the activation and function of protein kinase B. J Biol Chem 1997;272:31515–24.[Abstract/Free Full Text]
  19. Stegh AH, Schickling O, Ehret A, et al. DEDD, a novel death effector domain-containing protein, targeted to the nucleolus. EMBO J 1998;17:5974–86.[CrossRef][Medline]
  20. Horky M, Kotala V, Anton M, Wesierska-Gadek J. Nucleolus and apoptosis. Ann N Y Acad Sci 2002;973:258–64.[Abstract/Free Full Text]



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