Transcriptional regulation of the cyclin D1 gene at a glance.
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ABSTRACT:
SUBMITTER: Klein EA
PROVIDER: S-EPMC4545630 | biostudies-literature | 2008 Dec
REPOSITORIES: biostudies-literature
Publications
Transcriptional regulation of the cyclin D1 gene at a glance.
Klein Eric A EA Assoian Richard K RK
Journal of cell science 20081201 Pt 23
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Project description:Multiple signals control the balance between proliferation and differentiation of neural progenitor cells during corticogenesis. A key point of this regulation is the control of G1 phase length, which is regulated by the Cyclin/Cdks complexes. Using genome-wide chromatin immunoprecipitation assay and mouse genetics, we have explored the transcriptional regulation of Cyclin D1 (Ccnd1) during the early developmental stages of the mouse cerebral cortex. We found evidence that SP8 binds to the Ccnd1 locus on exon regions. In vitro experiments show SP8 binding activity on Ccnd1 gene 3'-end, and point to a putative role for SP8 in modulating PAX6-mediated repression of Ccnd1 along the dorso-ventral axis of the developing pallium, creating a medialLow-lateralHigh gradient of neuronal differentiation. Activation of Ccnd1 through the promoter/5'-end of the gene does not depend on SP8, but on βcatenin (CTNNB1). Importantly, alteration of the Sp8 level of expression in vivo affects Ccnd1 expression during early corticogenesis. Our results indicate that Ccnd1 regulation is the result of multiple signals and that SP8 is a player in this regulation, revealing an unexpected and potentially novel mechanism of transcriptional activation.
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Project description:Considering that 80 genomes have been sequenced, providing us with the static information of the genome, it is still a long way to reveal the relationship between complex genotypes and phenotypes. The transcriptional regulation process is one of the obstacles that need to be understood to bridge our current information gap. It describes the first step from the genomic sequence information to RNA templates used for protein production or as direct functional units, like non-coding RNAs (e.g. micro RNAs). This introduction aims to highlight the key aspects of the transcriptional process from our current understanding.
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Project description:The ETS family transcription factor ETV4 is aberrantly expressed in a variety of human tumors and plays an important role in carcinogenesis through upregulation of relevant target gene expression. Here, it is demonstrated that ETV4 is overexpressed in pancreatic cancer tissues as compared with the normal pancreas, and is associated with enhanced growth and rapid cell-cycle progression of pancreatic cancer cells. ETV4 expression was silenced through stable expression of a specific short hairpin RNA (shRNA) in two pancreatic cancer cell lines (ASPC1 and Colo357), while it was ectopically expressed in BXPC3 cells. Silencing of ETV4 in ASPC1 and Colo357 cells reduced the growth by 55.3% and 38.9%, respectively, while forced expression of ETV4 in BXPC3 cells increased the growth by 46.8% in comparison with respective control cells. Furthermore, ETV4-induced cell growth was facilitated by rapid transition of cells from G1- to S-phase of the cell cycle. Mechanistic studies revealed that ETV4 directly regulates the expression of Cyclin D1 CCND1, a protein crucial for cell-cycle progression from G1- to S-phase. These effects on the growth and cell cycle were reversed by the forced expression of Cyclin D1 in ETV4-silenced pancreatic cancer cells. Altogether, these data provide the first experimental evidence for a functional role of ETV4 in pancreatic cancer growth and cell-cycle progression.Implications: The functional and mechanistic data presented here regarding ETV4 in pancreatic cancer growth and cell-cycle progression suggest that ETV4 could serve as a potential biomarker and novel target for pancreatic cancer therapy. Mol Cancer Res; 16(2); 187-96. ©2017 AACR.
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Project description:Cyclin D1 expression represents one of the key mitogen-regulated events during the G(1) phase of the cell cycle, whereas Cyclin D1 overexpression is frequently associated with human malignancy. Here, we describe a novel mechanism regulating Cyclin D1 levels. We find that SNIP1, previously identified as a regulator of Cyclin D1 expression, does not, as previously thought, primarily function as a transcriptional coactivator for this gene. Rather, SNIP1 plays a critical role in cotranscriptional or posttranscriptional Cyclin D1 mRNA stability. Moreover, we show that the majority of nucleoplasmic SNIP1 is present within a previously undescribed complex containing SkIP, THRAP3, BCLAF1, and Pinin, all proteins with reported roles in RNA processing and transcriptional regulation. We find that this complex, which we have termed the SNIP1/SkIP-associated RNA-processing complex, is coordinately recruited to both the 3' end of the Cyclin D1 gene and Cyclin D1 RNA. Significantly, SNIP1 is required for the further recruitment of the RNA processing factor U2AF65 to both the Cyclin D1 gene and RNA. This study shows a novel mechanism regulating Cyclin D1 expression and offers new insight into the role of SNIP1 and associated proteins as regulators of proliferation and cancer.
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Project description:Cyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes, and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was proportional to cyclin D1 levels. This cyclin D1-dependent global transcriptional downregulation was associated with a reduced nascent transcription and an accumulation of promoter-proximal paused RNA polymerase II (Pol II) that colocalized with cyclin D1. Concordantly, cyclin D1 overexpression promoted an increase in the Poll II pausing index. This transcriptional impairment seems to be mediated by the interaction of cyclin D1 with the transcription machinery. In addition, cyclin D1 overexpression sensitized cells to transcription inhibitors, revealing a synthetic lethality interaction that was also observed in primary mantle cell lymphoma cases. This finding of global transcriptional dysregulation expands the known functions of oncogenic cyclin D1 and suggests the therapeutic potential of targeting the transcriptional machinery in cyclin D1-overexpressing tumors.
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Project description:Hepatic gluconeogenesis is crucial to maintain normal blood glucose during periods of nutrient deprivation. Gluconeogenesis is controlled at multiple levels by a variety of signal transduction and transcriptional pathways. However, dysregulation of these pathways leads to hyperglycemia and type 2 diabetes. While the effects of various signaling pathways on gluconeogenesis are well established, the downstream signaling events repressing gluconeogenic gene expression are not as well understood. The cell-cycle regulator cyclin D1 is expressed in the liver, despite the liver being a quiescent tissue. The most well-studied function of cyclin D1 is activation of cyclin-dependent kinase 4 (CDK4), promoting progression of the cell cycle. We show here a novel role for cyclin D1 as a regulator of gluconeogenic and oxidative phosphorylation (OxPhos) gene expression. In mice, fasting decreases liver cyclin D1 expression, while refeeding induces cyclin D1 expression. Inhibition of CDK4 enhances the gluconeogenic gene expression, whereas cyclin D1-mediated activation of CDK4 represses the gluconeogenic gene-expression program in vitro and in vivo. Importantly, we show that cyclin D1 represses gluconeogenesis and OxPhos in part via inhibition of peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α) activity in a CDK4-dependent manner. Indeed, we demonstrate that PGC1α is novel cyclin D1/CDK4 substrate. These studies reveal a novel role for cyclin D1 on metabolism via PGC1α and reveal a potential link between cell-cycle regulation and metabolic control of glucose homeostasis.
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Project description:The correlation between aberrant DNA methylation with cancer promotion and progression has prompted an interest in discerning the associated regulatory mechanisms. Kaiso (ZBTB33) is a specialized transcription factor that selectively recognizes methylated CpG-containing sites as well as a sequence-specific DNA target. Increasing reports link ZBTB33 overexpression and transcriptional activities with metastatic potential and poor prognosis in cancer, although there is little mechanistic insight into how cells harness ZBTB33 transcriptional capabilities to promote and progress disease. Here we report mechanistic details for how ZBTB33 mediates cell-specific cell cycle regulation. By utilizing ZBTB33 depletion and overexpression studies, it was determined that in HeLa cells ZBTB33 directly occupies the promoters of cyclin D1 and cyclin E1, inducing proliferation by promoting retinoblastoma phosphorylation and allowing for E2F transcriptional activity that accelerates G1- to S-phase transition. Conversely, in HEK293 cells ZBTB33 indirectly regulates cyclin E abundance resulting in reduced retinoblastoma phosphorylation, decreased E2F activity, and decelerated G1 transition. Thus, we identified a novel mechanism by which ZBTB33 mediates the cyclin D1/cyclin E1/RB1/E2F pathway, controlling passage through the G1 restriction point and accelerating cancer cell proliferation.
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Project description:Cyclin D1 is a cell cycle machine, a sensor of extracellular signals and plays an important role in G1-S phase progression. The human cyclin D1 promoter contains multiple transcription factor binding sites such as AP-1, NF-қB, E2F, Oct-1, and so on. The extracellular signals functions through the signal transduction pathways converging at the binding sites to active or inhibit the promoter activity and regulate the cell cycle progression. Different signal transduction pathways regulate the promoter at different time to get the correct cell cycle switch. Disorder regulation or special extracellular stimuli can result in cell cycle out of control through the promoter activity regulation. Epigenetic modifications such as DNA methylation and histone acetylation may involved in cyclin D1 transcriptional regulation.
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Project description:Low-dose chronic exposure to arsenic in drinking water represents a global public health concern with established risks for metabolic and cardiovascular disease, as well as cancer. While the linkage between arsenic and disease is strong, further understanding of the molecular mechanisms of its pathogenicity is required. Previous reports demonstrated the ability of arsenic to interfere with adipogenesis, which may mediate its effects in promoting metabolic disease. We hypothesized that microRNA are important regulators of most if not all mesenchymal stem cell processes that are dysregulated by arsenic exposure to impair lipogenesis. Arsenic increased the expression of miR-29b in white adipose tissue, as well as human mesenchymal stem cells (hMSCs) isolated from adipose tissue. Exposing hMSCs to arsenic increased abundance of miR-29b and cyclin D1 to promote proliferation over differentiation. Paradoxically, inhibition of miR-29b enhanced the inhibitory effect of arsenic on differentiation. This paradox was attributed to a requirement for miR-29 in regulating cyclin D1 expression as stable inhibition of miR-29b eliminated the cyclic pattern of cyclin D1 expression. Temporal regulation of cyclin D1 is critical for adipogenic differentiation, and the data suggest a paradigm where arsenic disruption of miR-29b regulatory pathways impairs adipogenic differentiation and ultimately adipose metabolic homeostasis.
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Project description:Cyclin D1 belongs to the core cell cycle machinery, and it is frequently overexpressed in human cancers. The full repertoire of cyclin D1 functions in normal development and oncogenesis is unclear at present. Here we developed Flag- and haemagglutinin-tagged cyclin D1 knock-in mouse strains that allowed a high-throughput mass spectrometry approach to search for cyclin D1-binding proteins in different mouse organs. In addition to cell cycle partners, we observed several proteins involved in transcription. Genome-wide location analyses (chromatin immunoprecipitation coupled to DNA microarray; ChIP-chip) showed that during mouse development cyclin D1 occupies promoters of abundantly expressed genes. In particular, we found that in developing mouse retinas-an organ that critically requires cyclin D1 function-cyclin D1 binds the upstream regulatory region of the Notch1 gene, where it serves to recruit CREB binding protein (CBP) histone acetyltransferase. Genetic ablation of cyclin D1 resulted in decreased CBP recruitment, decreased histone acetylation of the Notch1 promoter region, and led to decreased levels of the Notch1 transcript and protein in cyclin D1-null (Ccnd1(-/-)) retinas. Transduction of an activated allele of Notch1 into Ccnd1(-/-) retinas increased proliferation of retinal progenitor cells, indicating that upregulation of Notch1 signalling alleviates the phenotype of cyclin D1-deficiency. These studies show that in addition to its well-established cell cycle roles, cyclin D1 has an in vivo transcriptional function in mouse development. Our approach, which we term 'genetic-proteomic', can be used to study the in vivo function of essentially any protein.
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