Akt Inhibits the Orphan Nuclear Receptor Nur77 and T-cell Apoptosis

Masuyama, Norihisa; Oishi, Koji; Mori, Yasunori; Ueno, Tomoo; Takahama, Yousuke; Gotoh, Yukiko

doi:10.1074/jbc.m105431200

Cited by 140 publications

(137 citation statements)

References 35 publications

(46 reference statements)

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“…In the nucleus Akt phosphorylates or interacts with proteins implicated in apoptosis resistance, a pathway where Akt has a key role (Andjelkovic´et al, 1997;Masuyama et al, 2001;Ahn et al, 2006;Lee et al, 2008). Moreover, Akt proteins have been involved in the process of EMT (Thiery et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Akt2 interacts with Snail1 in the E-cadherin promoter

et al. 2011

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Snail1 is a transcriptional factor essential for triggering epithelial-to-mesenchymal transition. Moreover, Snail1 promotes resistance to apoptosis, an effect associated to PTEN gene repression and Akt stimulation. In this article we demonstrate that Snail1 activates Akt at an additional level, as it directly binds to and activates this protein kinase. The interaction is observed in the nucleus and increases the intrinsic Akt activity. We determined that Akt2 is the isoform interacting with Snail1, an association that requires the pleckstrin homology domain in Akt2 and the C-terminal half in Snail1. Snail1 enhances the binding of Akt2 to the E-cadherin (CDH1) promoter and Akt2 interference prevents Snail1 repression of CDH1 gene. We also show that Snail1 binding increases Akt2 intrinsic activity on histone H3 and have identified Thr45 as a residue modified on this protein. Phosphorylation of Thr45 in histone H3 is sensitive to Snail1 and Akt2 cellular levels; moreover, Snail1 upregulates the binding of phosphoThr45 histone H3 to the CDH1 promoter. These results uncover an unexpected role of Akt2 in transcriptional control and point out to phosphorylation of Thr45 in histone H3 as a new epigenetic mark related to Snail1 and Akt2 action.

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Section: Discussionmentioning

confidence: 99%

Akt2 interacts with Snail1 in the E-cadherin promoter

et al. 2011

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“…We, therefore, studied whether Akt, which is known to phosphorylate Nur77 (Masuyama et al, 2001;Pekarsky et al, 2001), was involved. First, we examined the effect of 3-Cl-AHPC on Akt activation in H460 cells, in which 3-Cl-AHPC-induced Nur77 nuclear export was rapid, occurring within 1-6 h (Li et al, 2000;Cao et al, 2004;Lin et al, 2004).…”

Section: Phosphorylation Of Nur77 By Mekk1and Its Regulation Of Nur77mentioning

confidence: 99%

“…Thus, Akt activation inhibited MEKK1-DA-induced Nur77 nuclear export. Human Nur77 is phosphorylated by Akt at Ser351 (Ser350 in rat Nur77) (Masuyama et al, 2001;Pekarsky et al, 2001). To study whether the effect of CA-Akt was due to its phosphorylation of Nur77, Ser351 of Nur77 was replaced with alanine.…”

Section: Phosphorylation Of Nur77 By Mekk1and Its Regulation Of Nur77mentioning

confidence: 99%

“…Thus, phosphorylation may play a role in regulating Nur77 subcellular trafficking. In fact, Nur77 is heavily phosphorylated in various cell types and phosphorylation regulates Nur77 functions (Fahrner et al, 1990;Hazel et al, 1991;Davis et al, 1993;Hirata et al, 1993;Weih et al, 1996;Katagiri et al, 2000;Masuyama et al, 2001;Pekarsky et al, 2001;Kolluri et al, 2003). Nur77 is phosphorylated at its N-terminal A/B domain by Jun N-terminal kinase (JNK) (Kolluri et al, 2003) and at Ser350 (Ser351 in human Nur77) by Akt (Masuyama et al, 2001;Pekarsky et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Nur77 is phosphorylated at its N-terminal A/B domain by Jun N-terminal kinase (JNK) (Kolluri et al, 2003) and at Ser350 (Ser351 in human Nur77) by Akt (Masuyama et al, 2001;Pekarsky et al, 2001). Nur77 phosphorylation by JNK and Akt modulates its DNA-binding and transactivation functions (Masuyama et al, 2001;Pekarsky et al, 2001;Kolluri et al, 2003). The role of phosphorylation in Nur77 nuclear export is demonstrated by the finding that nerve growth factor (NGF)-induced NGFI-B nuclear export requires the phosphorylation of NGFI-B at Ser105 (Ser140 in human Nur77) by MAP kinase pathway (Katagiri et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

et al. 2006

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Proapoptotic nuclear receptor family member Nur77 translocates from the nucleus to the mitochondria, where it interacts with Bcl-2 to trigger apoptosis. Nur77 translocation is induced by certain apoptotic stimuli, including the synthetic retinoid-related 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN)/ CD437 class. In this study, we investigated the molecular mechanism by which AHPN/CD437 analog (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces Nur77 nuclear export. Our results demonstrate that 3-Cl-AHPC effectively activated Jun N-terminal kinase (JNK), which phosphorylates Nur77. Inhibition of JNK activation by a JNK inhibitor suppressed 3-Cl-AHPC-induced Nur77 nuclear export and apoptosis. In addition, several JNK upstream activators, including the phorbol ester TPA, anisomycin and MAPK kinase kinase-1 (MEKK1), phosphorylated Nur77 and induced its nuclear export. However, Nur77 phosphorylation by JNK, although essential, was not sufficient for inducing Nur77 nuclear export. Induction of Nur77 nuclear export by MEKK1 required a prolonged MEKK1 activation and was attenuated by Akt activation. Expression of constitutively active Akt prevented MEKK1-induced Nur77 nuclear export. Conversely, transfection of dominant-negative Akt or treatment with a phosphatidylinositol 3-kinase (PI3-K) inhibitor accelerated MEKK1-induced Nur77 nuclear export. Furthermore, mutation of an Akt phosphorylation residue Ser351 in Nur77 abolished the effect of Akt or the PI3-K inhibitor. Together, our results demonstrate that both activation of JNK and inhibition of Akt play a role in translocation of Nur77 from the nucleus to the cytoplasm.

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Molecular Basis of Mature T-Cell Leukemia

Pekarsky

Hallas²,

Croce³

2001

JAMA

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T-cell chronic lymphocytic/prolymphocytic leukemia (T-CLL/T-PLL) is a lymphoproliferative disease derived from immunocompetent post-thymic T cells. Activation (initiation of expression) of the TCL1 locus at chromosome 14q32.1 appears to be the causal event in the pathogenesis of these mature T-cell leukemias. This activation occurs as a result of translocations or inversions that cause rearrangement of the TCL1 (T-cell leukemia/lymphoma 1) locus with regulatory elements of T-cell receptor genes. To describe the molecular events that take part in the leukemogenesis of mature T-cell leukemias, we reviewed the literature and our own data on the molecular basis of mature T-cell leukemia. This data search revealed that 4 genes have been identified at the TCL1 locus: TCL1, TCL1b, TNG1, and TNG2. The expression of these genes is substantially increased following rearrangements involving 14q32.1. Functional analysis of the Tcl1 protein revealed its involvement in an Akt (protein kinase B) prosurvival pathway through its interaction with the Akt kinase, which promotes translocation of Akt to the nucleus and increases Akt's enzymatic activity. The available data provide important insights into the molecular mechanisms of T-cell leukemogenesis that may lead to the development of new drugs for treatment of mature T-cell leukemia.

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Akt Inhibits the Orphan Nuclear Receptor Nur77 and T-cell Apoptosis

Cited by 140 publications

References 35 publications

Akt2 interacts with Snail1 in the E-cadherin promoter

Akt2 interacts with Snail1 in the E-cadherin promoter

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

Molecular Basis of Mature T-Cell Leukemia

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