Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE6838 | GEO | 2007/02/01
SECONDARY ACCESSION(S): PRJNA99129
REPOSITORIES: GEO
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Project description:The miR-16 family, which targets genes important for the G1-S transition, is a known modulator of the cell cycle, and members of this family are often deleted or down-regulated in many types of cancers. Here we report the reciprocal relationship - that of the cell cycle controlling the miR-16 family. Levels of this family increase rapidly as cells are arrested in G0. Conversely, as cells are released from G0 arrest, levels of the miR-16 family rapidly decrease. Such rapid changes are made possible by the unusual instabilities of several family members. The repression mediated by the miR-16 family is sensitive to these cell cycle changes, which suggests that the rapid up-regulation of the miR-16 family reinforces cell cycle arrest in G0. Upon cell cycle re-entry, the rapid decay of several members allows levels of the family to decrease, alleviating repression of target genes and allowing proper resumption of the cell cycle.
2011-09-15 | GSE31225 | GEO
Project description:The miR-16 family, which targets genes important for the G1-S transition, is a known modulator of the cell cycle, and members of this family are often deleted or down-regulated in many types of cancers. Here we report the reciprocal relationship - that of the cell cycle controlling the miR-16 family. Levels of this family increase rapidly as cells are arrested in G0. Conversely, as cells are released from G0 arrest, levels of the miR-16 family rapidly decrease. Such rapid changes are made possible by the unusual instabilities of several family members. The repression mediated by the miR-16 family is sensitive to these cell cycle changes, which suggests that the rapid up-regulation of the miR-16 family reinforces cell cycle arrest in G0. Upon cell cycle re-entry, the rapid decay of several members allows levels of the family to decrease, alleviating repression of target genes and allowing proper resumption of the cell cycle. Small RNAs were profiled by high-throughput sequencing either during synchronous release after serum starvation or during cell-cycle arrest by contact inhibition.
2011-09-15 | E-GEOD-31225 | biostudies-arrayexpress
Project description:In acute myeloid leukemia (AML), leukemia stem cells (LSC) play a central role in disease progression and recurrence due to their intrinsic capacity for self-renewal and chemotherapy resistance. Whereas epigenetic mechanisms balance normal blood stem cell self-renewal and fate decisions, mutation and dysregulation of epigenetic regulators are considered fundamental to leukemia initiation and progression. Alterations in miRNA function represent a non-canonical epigenetic mechanism influencing malignant hematopoiesis, however the function of miRNA in human LSC remains undetermined. Here we show that miRNA profiling of fractionated AML populations defines an LSC-specific signature that is highly prognostic for patient survival. Gain- and loss-of-function analyses demonstrated that miR-126 restrained cell cycle progression, prevented differentiation, and increased self-renewal of human LSC. By targeting the G0 to G1 gatekeeper CDK3, miR-126 preserved LSC quiescence and promoted chemotherapy resistance. Thus, in AML, miRNAs influence patient outcome through post-transcriptional regulation of stemness programs in LSC.
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Project description:Cell size and the cell cycle are intrinsically coupled and abnormal increases in cell size are associated with senescence and permanent cell cycle arrest. The mechanism by which overgrowth primes cells to withdraw from the cell cycle remains unknown. We investigate this here using CDK4/6 inhibitors that arrest cell cycle progression during G0/G1 and are used in the clinic to treat ER+/HER2- metastatic breast cancer. We demonstrate that CDK4/6 inhibition promotes cellular overgrowth during G0/G1, causing p38MAPK-p53-p21-dependent cell cycle withdrawal. We find that cell cycle withdrawal is triggered by two waves of p21 induction. First, overgrowth during a long-term G0/G1 arrest induces an osmotic stress response. This stress response produces the first wave of p21 induction. Second, when CDK4/6 inhibitors are removed, a fraction of cells escape long term G0/G1 arrest and enter S-phase where overgrowth-driven replication stress results in a second wave of p21 induction that causes cell cycle withdrawal from G2, or the subsequent G1. We propose a model whereby both waves of p21 induction contribute to promote permanent cell cycle arrest. This model could explain why cellular hypertrophy is associated with senescence and why CDK4/6 inhibitors have long-lasting effects in patients.
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Project description:The p53 tumour suppressor is a transcription factor that can regulate the expression of numerous genes encoding either proteins or microRNAs (miRNAs). The predominant outcomes of a typical p53 response are the initiation of apoptotic cascades and the activation of cell cycle checkpoints. HT29-tsp53 cells express a temperature sensitive variant of p53 and in the absence of exogenous DNA damage, these cells preferentially undergo G1 phase cell cycle arrest at the permissive temperature that correlates with increased expression of the cyclin-dependent kinase inhibitor p21WAF1. Recent evidence also suggests that a variety of miRNAs can induce G1 arrest by inhibiting the expression of proteins like CDK4 and CDK6. Here we used oligonucleotide microarrays to identify p53-regulated miRNAs that are induced in these cells undergoing G1 arrest. At the permissive temperature, the expression of several miRNAs was increased through a combination of either transcriptional or post-transcriptional regulation. In particular, miR-34a-5p, miR-143-3p and miR-145-5p were strongly induced and they reached levels comparable to that of reference miRNAs (miR-191 and miR-103). Importantly, miR-34a-5p and miR-145-5p are known to silence the Cdk4 and/or Cdk6 G1 cyclin-dependent kinases (cdks). Surprisingly, there was no p53-dependent decrease in the expression of either of these G1 cdks. To search for other potential targets of p53-regulated miRNAs, p53-downregulated mRNAs were identified through parallel microarray analysis of mRNA expression. Once again, there was no clear effect of p53 on the repression of mRNAs under these conditions despite a remarkable increase in p53-induced mRNA expression. Therefore, despite a strong p53 transcriptional response, there was no clear evidence that p53-responsive miRNA contributed to gene silencing. Taken together, the changes in cell cycle distribution in this cell line at the permissive temperature is likely attributable to transcriptional upregulation of the CDKN1A mRNA and p21WAF1 protein and not to the down regulation of CDK4 or CDK6 by p53-regulated miRNAs. Two independent experiments were performed with 2 samples in each experiment (1 control and 1 treatment condition). In the control sample, RNA was isolated cells maintained at the restrictive temperature (37ËC). The treatment treated sample, was incubated for 16 hours at the permissive temperature (32ËC).
2016-01-07 | E-GEOD-76576 | biostudies-arrayexpress
Project description:Cell cycle arrest in response to DNA damage is an important anti-tumorigenic mechanism. microRNAs (miRNAs) were shown recently to play key regulatory roles in cell cycle progression. For example, miR-34a is induced in response to p53 activation and mediates G1 arrest by down-regulating multiple cell cycle-related transcripts. Here we show that genotoxic stress promotes the p53-dependent up-regulation of the homologous miRNAs, miR -192 and miR-215. Like miR-34a, activation of miR-192/215 induces cell cycle arrest suggesting that multiple microRNA families operate in the p53 network. Furthermore, we define a downstream gene expression signature for miR-192/215 expression that includes a number of transcripts that regulate G1 and G2 checkpoints. Of these transcripts, 18 transcripts are direct targets of miR-192/215 and the observed cell cycle arrest likely results from a cooperative effect among the modulations of these genes by the miRNAs. Our results demonstrating a role for miR-192/215 in cell proliferation combined with recent observations that these miRNAs are under-expressed in primary cancers support the idea that miR-192 and miR-215 function as tumor-suppressors.
2008-12-07 | GSE13105 | GEO
Project description:Cell cycle arrest in response to DNA damage is an important anti-tumorigenic mechanism. microRNAs (miRNAs) were shown recently to play key regulatory roles in cell cycle progression. For example, miR-34a is induced in response to p53 activation and mediates G1 arrest by down-regulating multiple cell cycle-related transcripts. Here we show that genotoxic stress promotes the p53-dependent up-regulation of the homologous miRNAs, miR -192 and miR-215. Like miR-34a, activation of miR-192/215 induces cell cycle arrest suggesting that multiple microRNA families operate in the p53 network. Furthermore, we define a downstream gene expression signature for miR-192/215 expression that includes a number of transcripts that regulate G1 and G2 checkpoints. Of these transcripts, 18 transcripts are direct targets of miR-192/215 and the observed cell cycle arrest likely results from a cooperative effect among the modulations of these genes by the miRNAs. Our results demonstrating a role for miR-192/215 in cell proliferation combined with recent observations that these miRNAs are under-expressed in primary cancers support the idea that miR-192 and miR-215 function as tumor-suppressors. Description: Transfection of siRNA luc, miR-192 or miR-215 into HCT116 Dicerex5, compared to mock-transfected cells, with mRNA expression profiled at 10h and 24h post-transfection. Species: Human Tissue: HCT116 Dicerex5 cell line (tissue of origin = human colorectal carcinoma); this cell line is hypomorphic for Dicer gene function. Dye-swap: no Negative control: siRNA luc Replicates per each timepoint: no
2010-06-24 | E-GEOD-13105 | biostudies-arrayexpress
Project description:Cancer cachexia is a multifactorial metabolic syndrome defined by the rapid loss of skeletal muscle mass and the loss of fat mass. Up 80% of cancer patients at the late stage with cachexia suffer from progressive atrophy of adipose tissue. Unlike studies on skeletal muscle wasting, there is limited research on fat loss in cachexia. It was noted that most patients suffer from fat loss as cancer progress. Fat loss precedes muscle loss, is associated with shorter survival, and is variable to timing and intensity in various cancer populations. Increased lipolysis may be the leading cause of fat loss in cancer cachexia. miRNAs are a class of non-coding RNAs of 19~25 nucleotides that regulate gene silencing by interacting with the 3’ untranslated region (UTR) of target mRNA to cause mRNA degradation and translational repression. miRNAs play multifaceted roles in pancreatic cancer proliferation, survival, metastasis, and chemoresistance. Aberrant expression of miRNA in circulating exosomes may play potential roles in modulating fat loss in cancer cachexia. We identified 2 miRNAs, miR-16 and miR-29, which have 2-fold higher expression existed in at PDAC cells. To explore which genes in adipogenesis and lipolysis were directly affected by miR-16-5p or/and miR-29a-3p, we analyzed the targets which were down-regulated in both miR-16-5p and miR-29a-3p-transfected 3T3-L1 cells by mass analysis.
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Project description:Cancer cachexia is a multifactorial metabolic syndrome defined by the rapid loss of skeletal muscle mass and the loss of fat mass. Up 80% of cancer patients at the late stage with cachexia suffer from progressive atrophy of adipose tissue. Unlike studies on skeletal muscle wasting, there is limited research on fat loss in cachexia. It was noted that most patients suffer from fat loss as cancer progress. Fat loss precedes muscle loss, is associated with shorter survival, and is variable to timing and intensity in various cancer populations. Increased lipolysis may be the leading cause of fat loss in cancer cachexia. miRNAs are a class of non-coding RNAs of 19~25 nucleotides that regulate gene silencing by interacting with the 3’ untranslated region (UTR) of target mRNA to cause mRNA degradation and translational repression. miRNAs play multifaceted roles in pancreatic cancer proliferation, survival, metastasis, and chemoresistance. Aberrant expression of miRNA in circulating exosomes may play potential roles in modulating fat loss in cancer cachexia. We identified 2 miRNAs, miR-16 and miR-29, which have 2-fold higher expression existed in at PDAC cells. To explore which genes in adipogenesis and lipolysis were directly affected by miR-16-5p or/and miR-29a-3p, we analyzed the targets which were down-regulated in both miR-16-5p and miR-29a-3p-transfected 3T3-L1 cells by mass analysis.
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Project description:In acute myeloid leukemia (AML), leukemia stem cells (LSC) play a central role in disease progression and recurrence due to their intrinsic capacity for self-renewal and chemotherapy resistance. Whereas epigenetic regulation balances normal blood stem cell self-renewal and fate decisions, mutation and dysregulation of epigenetic modifiers are now considered fundamental to leukemia initiation and progression. Alterations in miRNA function represent a non-canonical epigenetic mechanism influencing malignant hematopoiesis, however the function of miRNA in LSC remains undetermined. Here we show that miRNA profiling of fractionated AML populations defines an LSC-specific signature that is highly predictive of patient survival. Gain of function genetic analysis demonstrated that miR-126 restrained cell cycle progression, prevented LSC differentiation, and increased LSC self-renewal. miR-126 promoted chemo-resistance, preserving LSC quiescence in part through suppression of the G0 to G1 gatekeeper, CDK3. Thus, in AML, miRNAs influence patient outcome through post-transcriptional regulation of stemness programs in LSC. 74 primary patient normal karyotype AML samples were analyzed for miRNA expression.
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