A Member of Forkhead Transcription Factor FKHRL1 Is a Downstream Effector of STI571-induced Cell Cycle Arrest in BCR-ABL-expressing Cells

Komatsu, Norio; Watanabe, Tomoko; Uchida, M.; Mori, Masaki; Kirito, Keita; Kikuchi, Shinichi; Liu, Qifa; Tauchi, Tetsuzo; Miyazawa, Kenji; Endo, Hitoshi; Nagai, Tadashi; Ozawa, Keiya

doi:10.1074/jbc.m211562200

Cited by 101 publications

(98 citation statements)

References 49 publications

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“…70 The forkhead family members AFX and FKHRL1 transcriptionally activate the p27 Kip1 gene and increase its RNA and protein levels. 66,70,71 Anti-HER2 antibodies, including trastuzumab, have been reported to inhibit the PI3K-AKT siganlings. 21,[24][25][26][27][28]62 As shown in Figure 3B, trastuzumab has no effect on total AKT expression but dramatically inhibits the enzymatic activity of AKT and both Ser473 and Thr308 phosphorylation.…”

Section: A B Cmentioning

confidence: 99%

HER2-targeting Antibodies Modulate the Cyclin-dependent Kinase Inhibitor p27Kip1 via Multiple Signaling Pathways

Pruefer

Bast³

2004

Cell Cycle

129

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Anti-HER2 antibody trastuzumab is emerging as a frontline therapy for patients with metastatic breast cancers that overexpress HER2. Understanding the molecular mechanisms by which the antibody inhibits tumor growth should permit the design of even more effective trastuzumab-based protocols. Several groups including our own have demonstrated that induction of cyclin-dependent kinase (CDK) inhibitor p27 Kip1 protein is one of the key mechanisms of action of HER2-targeting antibodies. In this review, we discuss currently available data regarding the multiple signaling targets and pathways by which HER2-targeting antibodies upregulate p27 Kip1 protein in breast cancer cells that overexpress HER2. Anti-HER2 antibodies inhibit HER2-mediated signaling in cancer cells, ultimately upregulating the levels and activity of p27 Kip1 protein. At least six signaling targets and pathways are modulated by trastuzumab. By inhibiting CDK2 and decreasing Thr187 phosphorylation of p27 Kip1 , trastuzumab abrogates targeting of SCF-ubiquitin E3 ligase and minimizes proteasome degradation of p27 Kip1 . By inhibiting AKT and human kinase interacting stathmin (hKIS), trastuzumab blocks Thr157-, Thr198-and Ser10-induced p27 Kip1 translocation from the nucleus to the cytosol, which increases the inhibitory effect of p27 Kip1 . By inhibiting Jun activation domain-binding protein 1 (Jab1) trastuzumab increases nuclear retention of p27 Kip1 . By inhibiting cyclin D and c-Myc, trastuzumab releases the sequestrated p27b Kip1 protein from cyclin D-CDK4/6 complexes and increase the effect of p27 Kip1 on CDK2-cyclin E complexes. By stimulating minibrain related kinase (MIRK), trastuzumab stabilizes p27 Kip1 in the nucleus, which increases inhibitory action of p27 Kip1 on CDK2. The targets and pathways affected by trastuzumab work in concert to maximize the expression and inhibitory effect of p27 Kip1 , which leads to cell cycle G 1 arrest and growth inhibition.

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Section: A B Cmentioning

confidence: 99%

HER2-targeting Antibodies Modulate the Cyclin-dependent Kinase Inhibitor p27Kip1 via Multiple Signaling Pathways

Pruefer

Bast³

2004

Cell Cycle

129

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“…Skorski et al (25) demonstrated that inhibition of PI3K downstream signaling by ectopic expression of dominant-negative PKB inhibited Bcr-Abldependent transformation of murine bone marrow cells in vitro and suppressed leukemia development in severe combined immunodeficiency disease (SCID) mice. In addition, recently it has been shown that FOXO3a was constitutively phosphorylated and therefore inactive in cell lines expressing Bcr-Abl (26,27). This suggests that inhibition of FOXO3a transcriptional activity may be required to maintain the leukemic phenotype.…”

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confidence: 99%

FOXO3a Induces Differentiation of Bcr-Abl-transformed Cells through Transcriptional Down-regulation of Id1

Birkenkamp

Essafi

Vos

et al. 2007

Journal of Biological Chemistry

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Homeostasis of the hematopoietic system requires tight control of proliferation, differentiation, and survival of progenitor cells (1-5). Combinations of cytokines acting on a progenitor cell initiate a specific developmental program through activation of distinct downstream signal-transduction pathways (6).Interference with this highly regulated process can lead to the development of hematopoietic malignancies. Myeloid transformation is often associated with chromosomal translocations and somatic mutations, affecting gene expression in ways that lead to defects in normal programs of cell proliferation, differentiation, and survival (7-12). For instance, chronic myeloid leukemia (CML) 9 is a lethal hematopoietic stem cell malignancy characterized by the t(9,22) chromosomal translocation, a translocation between the long arms of chromosomes 9 and 22, resulting in the formation of the Philadelphia (ph) chromosome and the fusion of a truncated bcr gene to the 5Ј-upstream sequences of the second exon of c-abl (9, 13). The bcr-abl fusion gene is known to be essential to the pathogenesis of CML, and the Bcr-Abl protein demonstrates constitutively active kinase activity, which is essential and sufficient for malignant transformation (9, 13, 14). Bcr-Abl exerts diverse actions on hematopoietic cells in terms of cellular transforming activity, inhibition of apoptosis, cell cycle progression, altered cell migration, and adhesion to extracellular matrix (9, 13, 14). Expression of Bcr-Abl results in growth factor independence of cells and activates multiple signaling cascades, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/c-Akt) signaling pathway (15,16).In non-malignant cells activation of the PI3K/PKB-signaling module is stimulated by growth factors and cytokines and has been linked to regulation of cellular proliferation and survival in a diverse variety of cell systems (17)(18)(19). Recently, it has been demonstrated that the members of the FOXO subfamily of transcription factors FOXO1, FOXO3a, and FOXO4 are directly phosphorylated by PKB (20,21). In the absence of growth or survival factors FOXOs are unphosphorylated, localized in the nucleus, and transcriptionally active. Upon stimulation with growth factors or cytokines, PKB activity is induced, and it translocates to the nucleus and phosphorylates FOXOs, leading to inhibition of transcriptional activity and nuclear export (22). We and others have demonstrated that FOXO transcription factors can regulate a variety of genes that influence cellular proliferation (e.g. p27 Kip1 and cyclin D), survival * This work was supported in part by the Dutch Scientific Organization (Grant NWO-90128139). 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. 31-30-250-4305; E-mail: P.J.Coffer@umcutrecht.nl. 9 The abbreviations used are: CML, chronic myeloid leukemia; PEPCK, phosphoenolpyruvate carboxykinase; PI3K, phosphatidyli...

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“…It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells [2][3][4] . Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemiainitiating cells (LICs) that drive the recurrence of CML [5][6][7][8] .…”

mentioning

confidence: 99%

TGF-β–FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia

Naka

Hoshii

Muraguchi

et al. 2010

Nature

543

508

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Chronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase 1 . It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells [2][3][4] . Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemiainitiating cells (LICs) that drive the recurrence of CML [5][6][7][8] . Here, using a syngeneic transplantation system and a CML-like myeloproliferative disease mouse model, we show that Foxo3a has an essential role in the maintenance of CML LICs. We find that cells with nuclear localization of Foxo3a and decreased Akt phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a 1/1 and Foxo3a 2/2 mice shows that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, we find that TGF-b is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-b inhibition, Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-b inhibitor impaired their colonyforming ability in vitro. Our results demonstrate a critical role for the TGF-b-FOXO pathway in the maintenance of LICs, and strengthen our understanding of the mechanisms that specifically maintain CML LICs in vivo.Although tyrosine kinase inhibitor (TKI) therapy of CML patients efficiently induces the death of leukaemia cells [5][6][7][8] , LICs in these patients can survive this therapy. To understand the molecular mechanisms maintaining CML LICs, we characterized LICs in vivo using a mouse model for CML-like myeloproliferative disease (MPD) 9 . Consistent with previous reports 10-13 , we found that a rare c-Kit 1 Lineage 2 (Lin 2 )Sca-1 1 (KLS 1 ) population of CML cells (that is, bearing markers of normal haematopoietic stem cells (HSCs)) induced efficient CML development in recipient mice (Supplementary Fig. 1). In contrast, neither c-Kit 1 Lin 2 Sca-1 2 (KLS 2 ) cells (which correspond to normal progenitors), nor other CML cell populations expressing differentiation markers, induced CML.We and others have shown that Foxo transcription factors, which are important downstream targets of PI3K-Akt signalling, are essential for the maintenance of self-renewal capacity in normal HSCs [14][15][16] . When a growth factor binds to the appropriate receptor, Akt is activated and phosphorylates Foxo proteins, resulting in their nuclear export and subsequent degradation in the cytoplasm. In the absence of growth factor stimulation, Foxo proteins are retained in an active state in the nucleus and induce their transcriptional targets. In CML cell lines, BCR-ABL is thought to activate PI3K-Akt signalling that leads to nuclear export of Foxo factors and suppression of their transcriptional activity...

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A Member of Forkhead Transcription Factor FKHRL1 Is a Downstream Effector of STI571-induced Cell Cycle Arrest in BCR-ABL-expressing Cells

Cited by 101 publications

References 49 publications

HER2-targeting Antibodies Modulate the Cyclin-dependent Kinase Inhibitor p27Kip1 via Multiple Signaling Pathways

HER2-targeting Antibodies Modulate the Cyclin-dependent Kinase Inhibitor p27Kip1 via Multiple Signaling Pathways

FOXO3a Induces Differentiation of Bcr-Abl-transformed Cells through Transcriptional Down-regulation of Id1

TGF-β–FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia

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