p27 suppresses cyclooxygenase-2 expression by inhibiting p38β and p38δ-mediated CREB phosphorylation upon arsenite exposure

Che, Xun; Liu, Jinyi; Huang, Haishan; Mi, Xiaoyi; Xia, Qing; Li, Jingxia; Zhang, Dongyun; Ke, Qingdong; Gao, Jimin; Huang, Chuanshu

doi:10.1016/j.bbamcr.2013.04.012

Cited by 13 publications

(10 citation statements)

References 65 publications

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“…Mutating the putative CRE sequences, but not SBE sites, severely reduced Stat3 promoter activity in p27 2/2 MEFs, indicating that p27 inhibited Stat3 transcription by abrogating CRE activity. Our results presented here are consistent with our recent finding that p27 suppresses Cox-2 transcription in a CREdependent manner during arsenite exposure (Che et al, 2013).…”

Section: /2supporting

confidence: 83%

Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration

Zhang

Wang

Liang

et al. 2014

Journal of Cell Science

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Cell migration is a dynamic process that is central to a variety of physiological functions as well as disease pathogenesis. The modulation of cell migration by p27 has been reported, but the exact mechanism(s) whereby p27 intersects with downstream effectors that control cell migration have not been elucidated. By systematically comparing p27+/+ MEFs with genetically ablated p27−/− MEFs using wound healing, transwell and time-lapse microscopic analyses, we provide direct evidence demonstrating that p27 inhibits both directional and random cell migration. Identical results were obtained with normal and cancer epithelial cells using complementary knockdown and overexpression approaches. Additional studies revealed that overexpression of manganese superoxide dismutase (MnSOD) and reduced intracellular oxidation played a key role in increased cell migration in p27-deficient cells. Furthermore, we identified signal transducer and activator of transcription 3 (STAT3) as the transcription factor responsible for p27-regulated MnSOD expression which was further mediated by ERKs/ATF1-dependent transactivation of CRE within the stat3 promoter. Collectively, our data strongly indicate that p27 plays a crucially negative role in cell migration by inhibiting MnSOD expression in a STAT-3 dependent manner.

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Section: /2supporting

confidence: 83%

Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration

Zhang

Wang

Liang

et al. 2014

Journal of Cell Science

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“…Our most recent studies demonstrated that acute exposure to 20μM arsenite shows comparable responses with chronic exposure to 1μM arsenite for two months [25]. Thus, arsenite dose of 20 μM was selected for current short term exposure.…”

Section: Resultsmentioning

confidence: 99%

NF-κB1 inhibits c-Myc protein degradation through suppression of FBW7 expression

Huang

et al. 2014

Oncotarget

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NF-κB is a well-known transcription factor in regulation of multiple gene transcription and biological processes, and most of them are relied on its transcriptional activity of the p65/RelA subunit, while biological function of another ubiquitously expressed subunit NF-κB1 (p50) remains largely unknown due to lack transcriptional activation domain. Here we discovered a novel biological function of p50 as a regulator of oncogenic c-Myc protein degradation upon arsenite treatment in a NF-κB transcriptional-independent mechanism. Our results found that p50 was crucial for c-Myc protein induction following arsenite treatment by using specific knockdown and deletion of p50 in its normal expressed cells as well as reconstituting expression of p50 in its deficient cells. Subsequently we showed that p50 upregulated c-Myc protein expression mainly through inhibiting its degradation. We also identified that p50 exhibited this novel property by suppression of FBW7 expression. FBW7 was profoundly upregulated in p50-defecient cells in comparison to that in p50 intact cells, whereas knockdown of FBW7 in p50-/- cells restored arsenite-induced c-Myc protein accumulation, assuring that FBW7 up-regulation was responsible for defect of c-Myc protein expression in p50-/- cells. In addition, we discovered that p50 suppressed fbw7 gene transcription via inhibiting transcription factor E2F1 transactivation. Collectively, our studies demonstrated a novel function of p50 as a regulator of c-Myc protein degradation, contributing to our notion that p50-regulated protein expression through multiple levels at protein translation and degradation, further providing a significant insight into the understanding of biomedical significance of p50 protein.

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“…As described in our previous studies (27, 32), dual-luciferase reporter assay was performed with the luciferase assay system (Promega Corp., Madison, WI). Each of the indicated luciferase reporter was transfected into human bladder cancer cells.…”

Section: Methodsmentioning

confidence: 99%

Role of STAT3 and FOXO1 in the Divergent Therapeutic Responses of Non-metastatic and Metastatic Bladder Cancer Cells to miR-145

Jiang

Huang

et al. 2017

Molecular Cancer Therapeutics

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Although miR-145 is the most frequently down-regulated miRNA in bladder cancer (BC), its exact stage-association and downstream effector have not been defined. Here, we found that miR-145 was upregulated in human BC patients with lymph node metastasis and in metastatic T24T cell line. Forced expression of miR-145 promoted anchorage-independent growth of T24T cells accompanied by the down-regulation of forkhead box class O1 (FOXO1). In contrast, in non-metastatic T24 cells, miR-145 overexpression inhibited cell growth with upregulation of FOXO1 and the knockdown of FOXO1 abolished the miR-145-mediated inhibition of cell growth. Mechanistic studies revealed that miR-145 directly bound to and attenuated 3′UTR activity of foxo1 mRNA in both T24 and T24T cells. Interestingly, miR-145 suppressed STAT3 phosphorylation at Tyr705 and increased foxo1 promoter transcriptional activity in T24 cells, but not in T24T cells, suggesting a role of STAT3 in the divergent responses to miR-145. Supporting this was our finding that STAT3 knockdown mimicked miR-145-mediated upregulation of FOXO1 in T24T cells and inhibition of anchorage-independent growth. Consistently, ectopic expression of miR-145 promoted tumor formation of xenograft T24T cells, whereas such promoting effect became inhibitory due to specific knockdown of STAT3. Together, our findings demonstrate the stage-specific association and function of miR-145 in BCs, and provide novel insights into the therapeutic targeting of miR-145.

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p27 suppresses cyclooxygenase-2 expression by inhibiting p38β and p38δ-mediated CREB phosphorylation upon arsenite exposure

Cited by 13 publications

References 65 publications

Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration

Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration

NF-κB1 inhibits c-Myc protein degradation through suppression of FBW7 expression

Role of STAT3 and FOXO1 in the Divergent Therapeutic Responses of Non-metastatic and Metastatic Bladder Cancer Cells to miR-145

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