Akt phosphorylates and suppresses the transactivation of retinoic acid receptor α

Honnappa, Srinivas; Xia, Dianren; Moore, Nicole L.; Uray, Iván P.; Kim, Heetae; Ma, Long; Weigel, Nancy L.; Brown, Powel H.; Kurie, Jonathan M.

doi:10.1042/bj20051794

Cited by 46 publications

(38 citation statements)

References 49 publications

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“…In previous years, there was a greater focus on the non-genomic regulation of RARα. Previous studies have identified that RARα may regulate the phosphoinositide 3-kinase, AKT, c-Jun N-terminal kinase, mitogen-activated protein kinase 14 and protein kinase C signaling pathways following abnormal translocation into the cytoplasm (10,(21)(22)(23). The present study identified that the overexpression of RARα was mainly located in the cytoplasm of LSCC cells and its downregulation significantly inhibited the activation of the AKT signaling pathway.…”

Section: Discussionsupporting

confidence: 47%

An oncogenic function of retinoic acid receptor‑α in the development of laryngeal squamous cell carcinoma

et al. 2017

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Abstract. The aberrant expression of retinoic acid receptor-α (RARα) has been reported in various types of cancer. However, its association with the prognosis and development of laryngeal squamous cell carcinoma (LSCC) has not yet been determined. Therefore, the present study aimed to examine the expression and function of RARα in patients with LSCC. The expression of RARα in LSCC tissues was investigated using immunostaining. An MTT assay and flow cytometry analysis were also performed to investigate the function of RARα in the proliferation and cell cycle of LSCC cells. The expression of RARα was significantly elevated in LSCC tissues compared with adjacent noncancerous tissues (78.1 vs. 6.3%, P<0.05). The overexpression of RARα was associated with poorly differentiated features of LSCC (P<0.05). Furthermore, the downregulation of RARα inhibited the proliferation of LSCC cells, and arrested the cell cycle at the G1 phase via upregulation of cyclin dependent kinase inhibitor 1A, which may be associated with inhibition of the protein kinase B signaling pathway. Therefore, the overexpression of RARα may contribute to the development of LSCC through the regulation of the cell cycle. The results of the present study provide evidence that RARα serves an important function in LSCC development and may be a potential therapeutic target or prognostic predictor for LSCC.

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Section: Discussionsupporting

confidence: 47%

An oncogenic function of retinoic acid receptor‑α in the development of laryngeal squamous cell carcinoma

et al. 2017

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“…Functional RAREs are present in the regulatory region of the human nephrin gene [25], and ATRA can induce expression of nephrin through activation of these regulatory elements. Recently, Srinivas et al report that Akt inhibited retinoid-induced transactivation in lung cancer cells via phosphorylation at the Ser96 residue of the RARa's DNA-binding domain [26]. Mutation of Ser96 to alanine abrogated the suppressive effect of Akt, and overexpression of a dominant-negative mutant of Akt decreased RAR phosphorylation and increased RAR transactivation.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional suppression of nephrin in podocytes by macrophages: Roles of inflammatory cytokines and involvement of the PI3K/Akt pathway

et al. 2007

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Expression of nephrin, a crucial component of the glomerular slit diaphragm, is downregulated in patients with proteinuric glomerular diseases. Using conditionally immortalized reporter podocytes, we found that bystander macrophages as well as macrophage-derived cytokines IL-1b and TNF-a markedly suppressed activity of the nephrin gene promoter in podocytes. The cytokine-initiated repression was reversible, observed on both basal and inducible expression, independent of Wilms' tumor suppressor WT1, and caused in part via activation of the phosphatidylinositol-3-kinase/Akt pathway. These results indicated a novel mechanism by which activated macrophages participate in the induction of proteinuria in glomerular diseases.

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“…p-Akt plays a central role in processes of tumorigenesis (36), and its levels have prognostic value in lung cancer (37). The retinoic acid receptor is a direct substrate of Akt (38) and cyclin-dependent kinase (39,40). A primary role of ALDH1A1 is to catalyze the conversion of retinol to retinoic acid (RA; refs.…”

Section: Discussionmentioning

confidence: 99%

β-Escin Inhibits NNK-Induced Lung Adenocarcinoma and ALDH1A1 and RhoA/Rock Expression in A/J Mice and Growth of H460 Human Lung Cancer Cells

Patlolla

Biddick

et al. 2013

Cancer Prevention Research

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Lung cancer is the leading cause of cancer-related deaths. b-Escin, a triterpene saponin isolated from horse chestnut seeds, was tested for inhibition of lung adenoma and adenocarcinoma induced by the tobacco carcinogen 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice; and its possible mode of action was evaluated using the H460 human lung cancer cell line. At 6 weeks of age, 35 mice were fed AIN-76A-modified diet, and one week later, lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 mmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed either control or experimental diets containing 500 ppm for 20 weeks (10 control, 5 b-escin) or 36 weeks (15 control, 5 b-escin) and evaluated for lung tumor via histopathologic methods. Administration of 500 ppm b-escin significantly suppressed lung tumor (adenoma þ adenocarcinoma) formation by more than 40% (P < 0.0015) at 20 weeks and by 53.3% (P < 0.0001) at 37 weeks. b-Escin inhibited NNK-induced lung adenocarcinoma formation by 65% (P < 0.001) at 20 weeks and by 53% (P < 0.0001) at 37 weeks. Immunohistochemical analysis revealed that lung tumors from mice exposed to b-escin showed significantly reduced aldehyde dehydrogenase (ALDH)1A1 and phospho-Akt (p-Akt) expression when compared with those in mice fed control diet. Aldefluor assay for ALDH revealed that among H460 lung cancer cells treated with different concentrations of b-escin (0-40 mmol/L), the subpopulation of cells with elevated ALDH activity was inhibited significantly. Our findings suggest that b-escin inhibits tobacco carcinogeninduced lung tumor formation by modulating ALDH1A1-positive cells and RhoA/Rock signaling. Cancer Prev Res; 6(10);

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Akt phosphorylates and suppresses the transactivation of retinoic acid receptor α

Cited by 46 publications

References 49 publications

An oncogenic function of retinoic acid receptor‑α in the development of laryngeal squamous cell carcinoma

An oncogenic function of retinoic acid receptor‑α in the development of laryngeal squamous cell carcinoma

Transcriptional suppression of nephrin in podocytes by macrophages: Roles of inflammatory cytokines and involvement of the PI3K/Akt pathway

β-Escin Inhibits NNK-Induced Lung Adenocarcinoma and ALDH1A1 and RhoA/Rock Expression in A/J Mice and Growth of H460 Human Lung Cancer Cells

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