scholarly journals TReP-132 Controls Cell Proliferation by Regulating the Expression of the Cyclin-Dependent Kinase Inhibitors p21WAF1/Cip1 and p27Kip1

2005 ◽  
Vol 25 (11) ◽  
pp. 4335-4348 ◽  
Author(s):  
Florence Gizard ◽  
Romain Robillard ◽  
Olivier Barbier ◽  
Brigitte Quatannens ◽  
Anne Faucompré ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Breast Tumor ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Mrna Levels ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
P27 Gene

ABSTRACT The transcriptional regulating protein of 132 kDa (TReP-132) has been identified in steroidogenic tissues, where it acts as a coactivator of steroidogenic factor 1 (SF-1). We show here that TReP-132 plays a role in the control of cell proliferation. In human HeLa cells, TReP-132 knockdown by using small interfering RNA resulted in increased G1→S cell cycle progression. The growth-inhibitory effects of TReP-132 was further shown to be mediated by induction of G1 cyclin-dependent kinase inhibitors p21WAF1 (p21) and p27KIP1 (p27) expression levels. As a consequence, G1 cyclin/cyclin-dependent kinase activities and pRB phosphorylation were markedly reduced, and cell cycle progression was blocked in the G1 phase. The stimulatory effect of TReP-132 on p21 and p27 gene transcription involved interaction of TReP-132 with the transcription factor Sp1 at proximal Sp1-binding sites in their promoters. Moreover, in different breast tumor cell lines, endogenous TReP-132 expression was positively related with a lower proliferation rate. In addition, TReP-132 knockdown resulted in enhanced cell proliferation and lowered p21 and p27 mRNA levels in the steroid-responsive and nonresponsive T-47D and MDA-MB-231 cell lines, respectively. Finally, a statistic profiling of human breast tumor samples highlighted that expression of TReP-132 is correlated with p21 and p27 levels and is associated with lower tumor incidence and aggressiveness. Together, these results identify TReP-132 as a basal cell cycle regulatory protein acting, at least in part, by interacting with Sp1 to activate the p21 and p27 gene promoters.

Induction of CABLES1 by the TKI Inhibits the Cell Cycle Progression and Induces Apoptosis In CML Cell.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1199-1199
Author(s):  
Tomonari Takemura ◽  
Satoki Nakamura ◽  
Yasuyuki Nagata ◽  
Daisuke Yokota ◽  
Isao Hirano ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Progenitor Cells ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Cycle Progression ◽  
Abl Kinase ◽  
Abl Kinase Inhibitors

Abstract Abstract 1199 [Background and Aims] CABLES1 (cyclin-dependent kinase (CDK)-5 and ABL enzyme 1) is a regulator of cell proliferation, apoptosis, and cell cycle, and it has been reported to be lost in a variety cancers. It has been also reported that knockout of the Cable1 gene has minimal to no effect on hematopoietic stem cells. However, we found that the expression of Cables1 gene and CABLES1 protein was suppressed in CML cells, and its function is little known in CML. In this study, we have investigated the function of CABLES1 in CML cell proliferation. [Methods] The cells used in this study were human CML cell lines, K562, Meg01 and SHG3 cells. Primary CML cells (ALDHhi cells) were obtained from the bone marrow of CML (CP) patients (n=12). Human normal ALDHhi cells were isolated from bone marrow of healthy volunteers after obtaining informed consents. For analysis of Cables1 mRNA expression, quantitative RT-PCR was performed in all cell lines treated with Abl kinase inhibitors (STI571, AMN107, and BMS354825). For cell survival analysis and the levels of p53 and some CDKIs in CML cells, MTT assays, western blot and cell cycle analysis were performed in all cell lines transfected with Cables1 shRNA or cDNA. For colony analysis, the colonies of CFU-GEMM, CFU-GM, and BFU-E were counted in CML stem/progenitor cells transfected with Cables1 cDNA or shiRNA, or treated with Abl kinase inhibitors. [Results] In CML cell lines, the expressions of Cables1 mRNA and CABLES1 protein were significantly increased by treatment with Abl kinase inhibitors or transfection with Bcr-Abl shRNA. In CML cells transfected with the Cables1 cDNA, it is shown that CML cell proliferation was inhibited, and the phosphorylation levels of p53, and the expression of BAX and p21 protein were markedly increased compared to the untransfected cells. In addition, the overexpression of CABLES1 induced G1 cell cycle arrest and reduced the DiOC6 fluorescence, indicating breakdown of the mitochondrial membrane potential in CML cells. On the other hand, the changes of p73 and p27 protein expression were not detected. Moreover, in CML cells transfected with Cables1 shRNA, the inhibition of CML cell proliferation by the Abl kinase inhibitors were weakened. In CML stem/progenitor cells (ALDHhi cells) obtained from patients with CML, the expression of Cables1 mRNA was suppressed, and the transfection with Bcr-Abl shRNA or treatment with Abl kinase inhibitors increased the expression of Cables1 mRNA and CABLES1 protein, and decreased the counts of CFU-GEMM, CFU-GM and BFU-E. [Conclusion] Our results demonstrated that the Bcr-Abl suppressed the expression of CABLES1, and the depletion of CABLES1 promotes cell cycle progression and p53-dependent apoptosis. Moreover, the induction of CABLES1 expression has the potentiality to eradicate CML stem/progenitor cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Roquin1 Suppresses Breast Cancer Growth by Inducing Cell Cycle Arrest via Selectively Destabilizing Cell Cycle–Promoting Gene mRNAs

2020 ◽  
Author(s):  
Wenbao Lu ◽  
Meicen Zhou ◽  
Bing Wang ◽  
Xueting Liu ◽  
Bingwei Li
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Breast Cancer Cell ◽  
Breast Tumor ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract Background: Dysregulation of cell cycle progression is one of the common features of human cancer cells, however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest induction in breast cancer.Methods: Public cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and the significant association with patient survival. Quantitative real-time PCR and western blots were performed to detect the expression of Roquin1 in breast cancer samples and cell lines. Cell counting, MTT assay, flow cytometry, and in vivo study were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA-sequencing was applied to identify the differential genes and pathways regulated by Roquin1. RNA immunoprecipitation assay, luciferase reporter assay, mRNA half-life detection, RNA affinity binding assay, and RIP-ChIP were used to explore the molecular mechanisms of Roquin1.Results: We showed that Roquin1 expression in breast cancer tissues and cell lines was inhibited, and the reduction in Roquin1 expression was associated with poor overall survival and relapse free survival of patients with breast cancer. Roquin1 overexpression inhibited breast cancer cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted breast cancer cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizing cell cycle–promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2) through targeting the stem–loop structure in the 3’untranslated region (3’UTR) of mRNAs via its ROQ domain, leading to the downregulation of cell cycle–promoting mRNAs.Conclusions: Our findings demonstrated that Roquin1 was a novel breast tumor suppressor and could induce G1/S cell cycle arrest by selectively downregulating the expression of cell cycle–promoting genes, which might as a potential molecular target for breast cancer treatment.

scholarly journals Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle–promoting genes

2020 ◽  
Author(s):  
Wenbao Lu ◽  
Meicen Zhou ◽  
Bing Wang ◽  
Xueting Liu ◽  
Bingwei Li
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Breast Tumor ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract Background: Dysregulation of cell cycle progression is a common feature of human cancer cells; however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest in breast cancer.Methods: Public cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and its association with patient survival. Quantitative real-time PCR and Western blots were performed to detect the expression of Roquin1 in breast cancer samples and cell lines. Cell counting, MTT assays, flow cytometry, and in vivo analyses were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA sequencing was applied to identify the differentially expressed genes regulated by Roquin1. RNA immunoprecipitation assay, luciferase reporter assay, mRNA half-life detection, RNA affinity binding assay, and RIP-ChIP were used to explore the molecular mechanisms of Roquin1.Results: We showed that Roquin1 expression in breast cancer tissues and cell lines was inhibited, and the reduction in Roquin1 expression was associated with poor overall survival and relapse-free survival of patients with breast cancer. Roquin1 overexpression inhibited cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizes cell cycle–promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2), by targeting the stem–loop structure in the 3' untranslated region (3'UTR) of mRNAs via its ROQ domain, leading to the downregulation of cell cycle–promoting mRNAs.Conclusions: Our findings demonstrated that Roquin1 is a novel breast tumor suppressor and could induce G1/S cell cycle arrest by selectively downregulating the expression of cell cycle–promoting genes, which might be a potential molecular target for breast cancer treatment.

scholarly journals Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle–promoting genes

2020 ◽  
Author(s):  
Wenbao Lu ◽  
Meicen Zhou ◽  
Bing Wang ◽  
Xueting Liu ◽  
Bingwei Li
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Breast Tumor ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract Background: Dysregulation of cell cycle progression is one of the common features of human cancer cells, however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest induction in breast cancer. Methods: Public cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and the significant association with patient survival. Quantitative real-time PCR and western blots were performed to detect the expression of Roquin1 in breast cancer samples and cell lines. Cell counting, MTT assay, flow cytometry, and in vivo study were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA-sequencing was applied to identify the differential genes and pathways regulated by Roquin1. RNA immunoprecipitation assay, luciferase reporter assay, mRNA half-life detection, RNA affinity binding assay, and RIP-ChIP were used to explore the molecular mechanisms of Roquin1. Results: We showed that Roquin1 expression in breast cancer tissues and cell lines was inhibited, and the reduction in Roquin1 expression was associated with poor overall survival and relapse free survival of patients with breast cancer. Roquin1 overexpression inhibited breast cancer cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted breast cancer cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizing cell cycle–promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2) through targeting the stem–loop structure in the 3’untranslated region (3’UTR) of mRNAs via its ROQ domain, leading to the downregulation of cell cycle–promoting mRNAs. Conclusions: Our findings demonstrated that Roquin1 was a novel breast tumor suppressor and could induce G1/S cell cycle arrest by selectively downregulating the expression of cell cycle–promoting genes, which might as a potential molecular target for breast cancer treatment.

scholarly journals Cortactin Modulates RhoA Activation and Expression of Cip/Kip Cyclin-Dependent Kinase Inhibitors To Promote Cell Cycle Progression in 11q13-Amplified Head and Neck Squamous Cell Carcinoma Cells

2010 ◽  
Vol 30 (21) ◽  
pp. 5057-5070 ◽  
Author(s):  
David R. Croucher ◽  
Danny Rickwood ◽  
Carole M. Tactacan ◽  
Elizabeth A. Musgrove ◽  
Roger J. Daly
Keyword(s):  
Cell Cycle ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
S Phase ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Fadu Cells ◽  
Phase Entry

ABSTRACT The cortactin oncoprotein is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC), often due to amplification of the encoding gene (CTTN). While cortactin overexpression enhances invasive potential, recent research indicates that it also promotes cell proliferation, but how cortactin regulates the cell cycle machinery is unclear. In this article we report that stable short hairpin RNA-mediated cortactin knockdown in the 11q13-amplified cell line FaDu led to increased expression of the Cip/Kip cyclin-dependent kinase inhibitors (CDKIs) p21WAF1/Cip1, p27Kip1, and p57Kip2 and inhibition of S-phase entry. These effects were associated with increased binding of p21WAF1/Cip1 and p27Kip1 to cyclin D1- and E1-containing complexes and decreased retinoblastoma protein phosphorylation. Cortactin regulated expression of p21WAF1/Cip1 and p27Kip1 at the transcriptional and posttranscriptional levels, respectively. The direct roles of p21WAF1/Cip1, p27Kip1, and p57Kip2 downstream of cortactin were confirmed by the transient knockdown of each CDKI by specific small interfering RNAs, which led to partial rescue of cell cycle progression. Interestingly, FaDu cells with reduced cortactin levels also exhibited a significant diminution in RhoA expression and activity, together with decreased expression of Skp2, a critical component of the SCF ubiquitin ligase that targets p27Kip1 and p57Kip2 for degradation. Transient knockdown of RhoA in FaDu cells decreased expression of Skp2, enhanced the level of Cip/Kip CDKIs, and attenuated S-phase entry. These findings identify a novel mechanism for regulation of proliferation in 11q13-amplified HNSCC cells, in which overexpressed cortactin acts via RhoA to decrease expression of Cip/Kip CDKIs, and highlight Skp2 as a downstream effector for RhoA in this process.

Restoration of microRNA-212 causes a G0/G1 cell cycle arrest and apoptosis in adult T-cell leukemia/lymphoma cells by repressing CCND3 expression

2016 ◽  
Vol 65 (1) ◽  
pp. 82-87 ◽  
Author(s):  
Haihao Wang ◽  
Qiannan Guo ◽  
Peiwen Yang ◽  
Guoxian Long
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
T Cell ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Cyclin D3 ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cycle Progression ◽  
Adult T Cell Leukemia

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive T-cell malignancy. This study was designed to explore the expression and functional significance of microRNA (miR)-212 in ATL. The expression of miR-212 in human ATL tissues and cell lines were investigated. Gain-of-function experiments were carried out to determine the roles of miR-212 in cell proliferation, tumorigenesis, cell cycle progression, and apoptosis. We also identified and functionally characterized the target genes of miR-212 in ATL cells. Compared with normal lymph node biopsies, lymphoma samples from ATL patients displayed underexpression of miR-212 (p=0.0032). Consistently, miR-212 was downregulated in human ATL cell lines, compared with normal T lymphocytes. Restoration of miR-212 significantly (p<0.05) inhibited ATL cell proliferation and tumorigenesis in mice. Overexpression of miR-212 led to an accumulation of G0/G1-phase cells and a concomitant reduction of S-phase cells. Moreover, enforced expression of miR-212-induced significant apoptosis in ATL cells. CCND3, which encodes a cell cycle regulator cyclin D3, was identified as a direct target of miR-212 in ATL cells. Rescue experiments with a miR-212-resistant variant of CCND3 demonstrated that overexpression of CCND3 restored cell-cycle progression and attenuated apoptotic response in miR-212-overexpressing ATL cells. Taken together, miR-212 exerts growth-suppressive effects in ATL cells largely by targeting CCND3 and may have therapeutic potential in ATL.

scholarly journals Expression of Cyclin-Dependent Kinase Inhibitors in Epiphyseal Chondrocytes Induced to Terminally Differentiate with Thyroid Hormone

Endocrinology ◽  
2000 ◽  
Vol 141 (12) ◽  
pp. 4552-4557 ◽  
Author(s):  
R. Tracy Ballock ◽  
Xiaolan Zhou ◽  
Lynn M. Mink ◽  
Daniel H. C. Chen ◽  
Barry C. Mita ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Thyroid Hormone ◽  
Cell Growth ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Terminal Differentiation ◽  
Cyclin Dependent Kinase ◽  
Growth Plate Chondrocytes ◽  
Cycle Progression ◽  
Cell Growth And Differentiation

Abstract A growing body of evidence suggests that systemic hormones and peptide growth factors may exert their effects on cell growth and differentiation in part through regulation of the cell division cycle. We hypothesized that thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through controlling cell cycle progression at the G1/S restriction point. Our results support this hypothesis by demonstrating that treatment of epiphyseal chondrocytes with thyroid hormone under chemically defined conditions results in the arrest of DNA synthesis and the onset of terminal differentiation, indicating that thyroid hormone is one factor capable of regulating the transition between cell growth and differentiation in these cells. This terminal differentiation process is associated with induction of the cyclin/cyclin-dependent kinase inhibitors p21cip-1, waf-1 and p27kip1, suggesting that thyroid hormone may regulate terminal differentiation in part by arresting cell cycle progression through induction of cyclin-dependent kinase inhibitors.

scholarly journals UBTF facilitates melanoma progression via modulating MEK1/2-ERK1/2 signalling pathways by promoting GIT1 transcription

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jian Zhang ◽  
Jiaojiao Zhang ◽  
Wenli Liu ◽  
Rui Ge ◽  
Tianyuan Gao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Melanoma Cell ◽  
Cell Cycle Progression ◽  
Signalling Pathways ◽  
Cell Multiplication ◽  
Cycle Progression ◽  
Qrt Pcr ◽  
Melanoma Cell Proliferation

Abstract Background UBTF is an HMGB-box DNA binding protein and a necessary Pol I/Pol II basal transcription factor. It has been found that UBTF involves in carcinogenesis and progression of a few cancers. Nevertheless, the the biological function and potential molecular mechanism of UBTF in melanoma are still not clear and need to be clarified. Methods UBTF and GIT1 expressions in melanoma specimens and cell lines were examined by quantitative real-time PCR (qRT-PCR) and Western blot. MTT and colony formation assays were used to investigate the effects of UBTF and GIT1 on melanoma cell proliferation. Cell cycle and apoptosis assays were detected by flow cytometry. Tumor formation assay was used to analyze the effect of UBTF on melanoma growth. Bioinformatics predicting, chromatin immunoprecipitation (ChIP)-qRT-PCR and reporter gene assay were fulfilled for verifing GIT1 as UBTF targeting gene. Results Here we reported that UBTF mRNA and protein expressions were upregulated in primary melanoma specimens and cell lines. UBTF overexpression facilitated melanoma cell proliferation and cell cycle progression and restrained. Silencing UBTF suppressed cell multiplication, cell cycle progression and tumor growth, and promoted apoptosis. UBTF expression was positively related with GIT1 expression in human melanoma tissues. It was verified that UBTF promoted GIT1 transcription in melanoma cells through binding to the promoter region of GIT1. Furthermore, GIT1 overexpression promoted melanoma cell growth and suppressed apoptosis. Knockdown of GIT1 inhibited cell multiplication and induced apoptosis. Overexpression of GIT1 eliminated the effects of silencing UBTF on melanoma cells. Importantly, UBTF activated MEK1/2-ERK1/2 signalling pathways by upregulating GIT1 expression. Conclusions Our study demonstrates that UBTF promotes melanoma cell proliferation and cell cycle progression by promoting GIT1 transcription, thereby activating MEK1/2-ERK1/2 signalling pathways. The findings indicate that UBTF plays a crucial function in melanoma and may be a potential therapeutic target for the treatment of this disease.

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