Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins

Bouchard, Caroline; Marquardt, Judith; Bras, Alexandra Le; Medema, René H.; Eilers, Martin

doi:10.1038/sj.emboj.7600279

Cited by 183 publications

(179 citation statements)

References 40 publications

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“…GSK3b is phosphorylated by Akt at serine 9 and consequently inactivated (Shaw et al, 1997). FoxO1 is a transcriptional regulator that controls the expression of several genes involved in cell proliferation, including p21 Cip1 (Seoane et al, 2004) and cyclin D2 (Bouchard et al, 2004). FoxO1 is phosphorylated by Akt on threonine 24 and serine 253 which then results in nuclear exclusion (Biggs et al, 1999;Brunet et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Oncogenic signaling of class I PI3K isoforms

et al. 2007

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The catalytic subunits of class I PI3Ks comprise four isoforms: p110a, p110b, p110d and p110c. Cancer-specific gain-of-function mutations in p110a have been identified in various malignancies. Cancer-specific mutations in the non-a isoforms of class I PI3K have not yet been identified, however overexpression of either wild-type p110b, p110c or p110d is sufficient to induce cellular transformation in chicken embryo fibroblasts. The mechanism whereby these non-a isoforms of class I mediate oncogenic signals is unknown. Here we show that potently transforming class I isoforms signal via Akt/mTOR, inhibit GSK3b and cause degradation of FoxO1. A functional Erk pathway is required for p110c and p110b transformation but not for transformation by p110d or the H1047R mutant of p110a. Transformation and signaling by p110c and p110b are sensitive to loss of interaction with Ras, which acts as a membrane anchor. Mutations in the C2 domain of p110d reduce transformation, most likely by interfering with membrane association. Several small molecule inhibitors potently and specifically inhibit the oncogenic signaling and transformation of each of the class I PI3K, and, when used in combination with MEK inhibitors, can additively reduce the transformation induced by p110b and p110c.

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Section: Discussionmentioning

confidence: 99%

Oncogenic signaling of class I PI3K isoforms

et al. 2007

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“…A notable feature of this mechanism is that polymerase occupancy is already high at the uninduced cad promoter and does not increase further in response to c-Myc (22,24). Activation of each of five other c-Myc targets examined also involved no apparent increase in the occupancy of pol II (24). In contrast, loading of P-TEFb, TFIIH, and Mediator increased at these promoters in response to c-Myc (24).…”

mentioning

confidence: 94%

“…In this case, c-Myc recruits the kinase P-TEFb, which may phosphorylate preassembled pol II and thereby stimulate promoter clearance and transcript elongation (22)(23)(24). A notable feature of this mechanism is that polymerase occupancy is already high at the uninduced cad promoter and does not increase further in response to c-Myc (22,24). Activation of each of five other c-Myc targets examined also involved no apparent increase in the occupancy of pol II (24).…”

mentioning

confidence: 99%

“…For example, activation of the cad promoter by c-Myc does not require recruitment of TRRAP and associated HATs and involves little change in histone acetylation (21,22). In this case, c-Myc recruits the kinase P-TEFb, which may phosphorylate preassembled pol II and thereby stimulate promoter clearance and transcript elongation (22)(23)(24). A notable feature of this mechanism is that polymerase occupancy is already high at the uninduced cad promoter and does not increase further in response to c-Myc (22,24).…”

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confidence: 99%

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TRRAP and GCN5 are used by c-Myc to activate RNA polymerase III transcription

Kenneth

Ramsbottom

Gomez-Roman

et al. 2007

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

103

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Activation of RNA polymerase (pol) II transcription by c-Myc generally involves recruitment of histone acetyltransferases and acetylation of histones H3 and H4. Here, we describe the mechanism used by c-Myc to activate pol III transcription of tRNA and 5S rRNA genes. Within 2 h of its induction, c-Myc appears at these genes along with the histone acetyltransferase GCN5 and the cofactor TRRAP. At the same time, occupancy of the pol III-specific factor TFIIIB increases and histone H3 becomes hyperacetylated, but increased histone H4 acetylation is not detected at these genes. The rapid acetylation of histone H3 and promoter assembly of TFIIIB, c-Myc, GCN5, and TRRAP are followed by recruitment of pol III and transcriptional induction. The selective acetylation of histone H3 distinguishes pol III activation by c-Myc from mechanisms observed in other systems.acetyltransferase ͉ chromatin ͉ histone ͉ TFIIIB ͉ TFIIIC

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“…For example, HDAC inhibitors have been shown to suppress MYC transcription, in part by upregulating the transcription of MYC suppressor genes, such as FOXO1, in some (14)(15)(16)(17) but not all cancer types (18). HDACs also facilitate MYC's oncogenic function as a transcription factor, as they are often recruited to the promoter regions of some MYC-targeted genes to facilitate MYC-mediated regulation of transcription.…”

Section: Introductionmentioning

confidence: 99%

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers

Sun

Atoyan

Borek

et al. 2017

Molecular Cancer Therapeutics

113

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Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDAC) and phosphoinositide 3-kinases (PI3K), can reduce MYC protein levels and suppress the growth of MYCdriven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear. In this study, we demonstrated that HDAC and PI3K inhibition synergistically downregulates MYC protein levels and induces apoptosis in "double-hit" (DH) diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, CUDC-907, a small-molecule dual-acting inhibitor of both class I and II HDACs and class I PI3Ks, effectively suppresses the growth and survival of MYC-altered or MYC-dependent cancer cells, such as DH DLBCL and BRD-NUT fusion-positive NUT midline carcinoma (NMC) cells, and MYC protein downregulation is an early event induced by CUDC-907 treatment. Consistently, the antitumor activity of CUDC-907 against multiple MYC-driven cancer types was also demonstrated in animal models, including DLBCL and NMC xenograft models, Myc transgenic tumor syngeneic models, and MYC-amplified solid tumor patient-derived xenograft (PDX) models. Our findings suggest that dual function HDAC and PI3K inhibitor CUDC-907 is an effective agent targeting MYC and thus may be developed as potential therapy for MYCdependent cancers.

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Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins

Cited by 183 publications

References 40 publications

Oncogenic signaling of class I PI3K isoforms

Oncogenic signaling of class I PI3K isoforms

TRRAP and GCN5 are used by c-Myc to activate RNA polymerase III transcription

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers

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