Transcriptional Regulation of Serine/Threonine Protein Kinase (AKT) Genes by Glioma-associated Oncogene Homolog 1

Agarwal, Nitin; Qu, Changju; Kunkulla, Kranthi; Liu, Yadong; Vega, Francisco

doi:10.1074/jbc.m112.425249

Cited by 38 publications

(27 citation statements)

References 54 publications

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“…Other groups have shown that the AKT1 promoter possesses two GLI1 binding sites (BS1 and BS2) and proved the expression of AKT1 was regulated at the transcriptional level by GLI131. Our results suggested that for AML patients with both GLI1 and AKT activation, the GLI1 inhibitor alone is sufficient, which will significantly decrease the unnecessary side effects of the combination therapy using Hh and PI3K inhibitors.…”

Section: Discussionsupporting

confidence: 59%

Targeting the PI3K/AKT pathway via GLI1 inhibition enhanced the drug sensitivity of acute myeloid leukemia cells

Liang

Zheng

Peng

et al. 2017

Sci Rep

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Combination targeted therapy is commonly used to treat acute myeloid leukemia (AML) patients, particularly in refractory/relapse (RR) population. However, concerns have been raised regarding the safety and patient tolerance of combination chemotherapy. It is critical to choose the appropriate treatment for precision therapy. We performed genome-wide RNA profiling using RNA-Seq to compare the RR group and the complete remission (CR) group (a total of 42 adult AML patients). The Hedgehog (Hh) and PI3K/AKT pathways were upregulated in the RR population, which was further confirmed by western blot and/or qPCR. Overexpression of GLI1 in AML cells led to increased AKT phosphorylation and decreased drug sensitivity, which was attenuated by GLI1 inhibition. By contrast, neither the expression of GLI1 nor apoptosis in response to Ara-C treatment of AML cells was significantly affected by PI3K inhibition. Furthermore, co-inhibition of GLI1 and PI3K induced apoptosis of hematopoietic stem/progenitor cells (HSPCs), which raised serious concerns about the side effects of this treatment. These results indicated that GLI1 inhibition alone, but not combined inhibition, is sufficient to enhance AML drug sensitivity, which provides a novel therapeutic strategy for AML treatment.

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Section: Discussionsupporting

confidence: 59%

Targeting the PI3K/AKT pathway via GLI1 inhibition enhanced the drug sensitivity of acute myeloid leukemia cells

Liang

Zheng

Peng

et al. 2017

Sci Rep

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“…GLI1, a zinc finger transcriptional factor of the Hedgehog signaling, increases the transcription of of AKT1, AKT2 , and AKT3 genes [32]. AKT1 promoter possesses two GLI1 binding sites (BS1 and BS2) located upstream of the transcriptional start site of AKT1 gene.…”

Section: Upstream Regulatory Pathways Of Aktmentioning

confidence: 99%

“…The homology of each GLI1 binding site to the consensus sequence was 67% for BS1 and 78% for BS2. AKT2 and AKT3 promoters also contain three and two GLI1 binding sites, respectively [32]. …”

Section: Upstream Regulatory Pathways Of Aktmentioning

confidence: 99%

The critical role of Akt in cardiovascular function

Abeyrathna

2015

Vascular Pharmacology

348

222

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Akt kinase, a member of AGC kinases, is important in many cellular functions including proliferation, migration, cell growth and metabolism. There are three known Akt isoforms which play critical and diverse roles in the cardiovascular system. Akt activity is regulated by its upstream regulatory pathways at transcriptional and post-translational levels. beta-catenin/Tcf-4, GLI1 and Stat-3 are some of few known transcriptional regulators of AKT gene. Threonine 308 and serine 473 are the two critical phosphorylation sites of Akt1. Translocation of Akt to the cell membrane facilitates PDK1 phosphorylation of the threonine site. The serine site is phosphorylated by mTORC2. Ack1, Src, PTK6, TBK1, IKBKE and IKKε are some of the non-canonical pathways which affect the Akt activity. Protein-protein interactions of Akt to actin and Hsp90 increase the Akt activity while Akt binding to other proteins such as CTMP and TRB3 reduces the Akt activity. The action of Akt on its downstream targets determines its function in cardiovascular processes such as cell survival, growth, proliferation, angiogenesis, vasorelaxation, and cell metabolism. Akt promotes cell survival via caspase-9, YAP, Bcl-2, and Bcl-x activities. Inhibition of FoxO proteins by Akt also increases cell survival by transcriptional mechanisms. Akt stimulates cell growth and proliferation through mTORC1. Akt also increases VEGF secretion and mediates eNOS phosphorylation, vasorelaxation and angiogenesis. Akt can increase cellular metabolism through its downstream targets GSK3 and GLUT4. The alterations of Akt signaling play an important role in many cardiovascular pathological processes such as atherosclerosis, cardiac hypertrophy, and vascular remodeling. Several Akt inhibitors have been developed and tested as anti-tumor agents. They could be potential novel therapeutics for the cardiovascular diseases.

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“…Moreover, regulation of cMYC [71,72] and possibly of AKT [73] by GLI1, may establish positive feed-forward loops. Together, this insures that GLI1 activity will increase as tumor suppressors are lost and oncogenes gained.…”

Section: Regulation Of the Gli Code By Non-hh Signals And By The Oncomentioning

confidence: 99%

Context-dependent signal integration by the GLI code: The oncogenic load, pathways, modifiers and implications for cancer therapy

Aberger

Altaba

2014

Seminars in Cell & Developmental Biology

146

175

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Canonical Hedgehog (HH) signaling leads to the regulation of the GLI code: the sum of all positive and negative functions of all GLI proteins. In humans, the three GLI factors encode context-dependent activities with GLI1 being mostly an activator and GLI3 often a repressor. Modulation of GLI activity occurs at multiple levels, including by co-factors and by direct modification of GLI structure. Surprisingly, the GLI proteins, and thus the GLI code, is also regulated by multiple inputs beyond HH signaling. In normal development and homeostasis these include a multitude of signaling pathways that regulate proto-oncogenes, which boost positive GLI function, as well as tumor suppressors, which restrict positive GLI activity. In cancer, the acquisition of oncogenic mutations and the loss of tumor suppressors – the oncogenic load – regulates the GLI code toward progressively more activating states. The fine and reversible balance of GLI activating GLIA and GLI repressing GLIR states is lost in cancer. Here, the acquisition of GLIA levels above a given threshold is predicted to lead to advanced malignant stages. In this review we highlight the concepts of the GLI code, the oncogenic load, the context-dependency of GLI action, and different modes of signaling integration such as that of HH and EGF. Targeting the GLI code directly or indirectly promises therapeutic benefits beyond the direct blockade of individual pathways.

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Transcriptional Regulation of Serine/Threonine Protein Kinase (AKT) Genes by Glioma-associated Oncogene Homolog 1

Cited by 38 publications

References 54 publications

Targeting the PI3K/AKT pathway via GLI1 inhibition enhanced the drug sensitivity of acute myeloid leukemia cells

Targeting the PI3K/AKT pathway via GLI1 inhibition enhanced the drug sensitivity of acute myeloid leukemia cells

The critical role of Akt in cardiovascular function

Context-dependent signal integration by the GLI code: The oncogenic load, pathways, modifiers and implications for cancer therapy

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