Cyclin D1 harboring the T286I mutation promotes oncogenic activation in endometrial cancer

Ikeda, Yuji; Oda, Katsutoshi; Hiraike‐Wada, Osamu; Koso, Takahiro; Miyasaka, Aki; Kashiyama, Tomoko; Sone, Kenbun; Nagasaka, Kazunori; Maeda, Daichi; Kawana, Kei; Nakagawa, Shunsuke; Fukayama, Masashi; Tetsu, Osamu; Fujii, Tomoyuki; Yano, Tetsu; Kozuma, Shiro

doi:10.3892/or.2013.2515

Cited by 14 publications

(20 citation statements)

References 28 publications

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“…Mutation, amplification and over-expression of CCND1 may alter the cell cycle process. These phenomena frequently occur in numerous types of cancer and may cause the development of tumors (49). The present study hypothesizes that miR-4458 may be developed and utilized in the future as a miR drug for the treatment of cancer.…”

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confidence: 83%

Role of microRNA-4458 in patients with non-small-cell lung cancer

et al. 2016

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Abstract. Incidence and progression of non-small-cell lung cancer (NSCLC) is a multi-factor, multi-step process. The present study investigated the association between the expression level of microRNA (miR)-4458 in NSCLC and paracarcinoma liver tissues and survival rates, and studied the biological functions of miR-4458 at the cellular and protein level. NSCLC and paracarcinoma tissues were sequenced using a miR expression chip. The association between miR-4458 expression and tumor-node-metastasis staging, total survival rate and relapse-free survival rate was analyzed. miR-4458 was subjected to target gene prediction. The target protein of cyclin D1 (CCND1) was verified with western blot analysis, immunohistochemistry and a luciferase reporter assay. The relative level of miR-4458 in paracarcinoma tissues of 9 NSCLC patients decreased from 2.38 to 0.65 (P<0.001). Total five-year survival rates of the high-expression miR-4458 group (29.21%) significantly exceeded that of the low-expression group (14.37%) (P=0.025). The viability of human lung carcinoma A549 and H460 cells transfected with miR-4458 decreased significantly compared with cells transfected with a normal control (blank control plasmid) within 72 h (P<0.001). The percentage of A549 and H460 cells transfected with a miR-4458 mimic at the cell cycle stage G0/G1 was 69.94±8.05 and 68.15±7.75%, respectively. The percentages increased significantly compared with the control group (46.06±6.93 for A549 cells; 45.22±7.24 for H640 cells; P<0.001). CCND1 mRNA was downregulated significantly in H460 cells 72 h subsequent to the addition of miR-4458 mimics (P<0.001). The activity of mutant-CCND1 altered slightly, while the fluorescence intensity of the wild-type-CCND1 group decreased significantly following the addition of miR-4458 mimics. In conclusion, miR-4458 was expressed at low levels in lung cancer tissues, and it arrested cells in vitro at stage G0/G1 and inhibited cell proliferation. Therefore, miR-4458 may participate in the onset of lung cancer as a suppressor gene by inhibiting CCND1.

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confidence: 83%

Role of microRNA-4458 in patients with non-small-cell lung cancer

et al. 2016

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“…The complex nature of the regulation of cyclin D1 degradation offers multiple target sites for tumorigenic alterations that could promote cyclin D1 stability. Direct degron mutations are relatively rare, although degron mutations are connected to endometrial cancer (230,231). Instead, the primary mechanism for E3 ligasedegron binding disruption is mutations in the SCF and CRL7 target recognition components.…”

Section: Disruption Of Synergistic Degrons and The Corresponding E3 Lmentioning

confidence: 99%

Degrons in cancer

et al. 2017

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Degrons are the elements that are used by E3 ubiquitin ligases to target proteins for degradation. Most degrons are short linear motifs embedded within the sequences of modular proteins. As regulatory sites for protein abundance, they are important for many different cellular processes, such as progression through the cell cycle and monitoring cellular hypoxia. Degrons enable the elimination of proteins that are no longer required, preventing their possible dysfunction. Although the human genome encodes~600 E3 ubiquitin ligases, only a fraction of these enzymes have well-defined target degrons. Thus, for most cellular proteins, the destruction mechanisms are poorly understood. This is important for many diseases, especially for cancer, a disease that involves the enhanced expression of oncogenes and the persistence of encoded oncoproteins coupled with reduced abundance of tumor suppressors. Lossof-function mutations occur in the degrons of several oncoproteins, such as the transcription factors MYC and NRF2, and in various mitogenic receptors, such as NOTCH1 and several receptor tyrosine kinases. Mutations eliminating the function of the b-catenin degron are found in many cancers and are considered one of the most abundant mutations driving carcinogenesis. In this Review, we describe the current knowledge of degrons in cancer and suggest that increased research on the "dark degrome" (unknown degron-E3 relationships) would enhance progress in cancer research.

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“…A gain of function mutation in KRAS activates both the mitogen‐activated protein kinase (MAPK) pathway and the PI3K pathway, whereas a loss of function mutation in PTEN activates the PI3K pathway . In addition to these alterations, we found various types of mutations in the RAS/PI3K pathway, including PIK3CA , AKT1 , and reduction in the chromosomal copy number of NF1 (a negative regulator of RAS) . Increased alteration in the activation of the RAS/PI3K pathway was confirmed based on TCGA .…”

Section: Coexistent Activating Mutations In the Ras/pi3k Pathway Potementioning

confidence: 57%

“…Cyclin D1 is downregulated by GSK3β, whereas AKT negatively regulates GSK3β function through phosphorylation of GSK3β on Ser‐9 . We reported that the CCND1 mutation (T286I), which was detected in two endometrial cancer specimens, increased cell proliferation . Furthermore, cyclin‐dependent kinase 4/6 specific activity (CDK4/6SA), which cooperates with cyclin D1 to promote the cell cycle, was a prognostic factor in endometrial cancer .…”

Section: Other Molecular‐targeted Therapies Related To Tp53 and Pi3k/mentioning

confidence: 99%

Characterization of TP53 and PI3K signaling pathways as molecular targets in gynecologic malignancies

Oda

Ikeda

Kashiyama

et al. 2016

J of Obstet and Gynaecol

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Recent developments in genomic analysis have unveiled the key signaling pathways in human cancer. However, only a limited number of molecular-targeted drugs are applicable for clinical use in gynecologic malignancies. TP53 signaling and phosphatidylinositol 3 kinase pathways are frequently mutated in cancer, and have received much attention as molecular targets in human cancers. In this review, we mainly focus on the functions of these pathways, and discuss the molecular-targeted drugs under clinical trials. The molecular-targeted drugs described in this review include dual phosphatidylinositol 3 kinase/mTOR inhibitors (NVP-BEZ235, DS-7423, SAR245409), an mTOR inhibitor (everolimus), an MEK inhibitor (pimasertib), an autophagy inhibitor (chloroquine), a cyclin-dependent kinases 4/6 inhibitor (PD0332991), and a poly (ADP-ribose) polymerase inhibitor (olaparib).

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Cyclin D1 harboring the T286I mutation promotes oncogenic activation in endometrial cancer

Cited by 14 publications

References 28 publications

Role of microRNA-4458 in patients with non-small-cell lung cancer

Role of microRNA-4458 in patients with non-small-cell lung cancer

Degrons in cancer

Characterization of TP53 and PI3K signaling pathways as molecular targets in gynecologic malignancies

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