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RABL6A promotes G1-S phase progression and pancreatic neuroendocrine tumor cell proliferation in an Rb1-dependent manner

ABSTRACT: Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs (PNETs) that correlated with high level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor suppressor pathways in the arrested cells. Specific inactivation of p53 had no effect on the RABL6A knockdown phenotype, indicating RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation restored G1 to S phase progression in RABL6A knockdown cells although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a new negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE53778 | GEO | 2014/07/01

SECONDARY ACCESSION(S): PRJNA232858

REPOSITORIES: GEO

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RABL6A promotes G1-S phase progression and pancreatic neuroendocrine tumor cell proliferation in an Rb1-dependent manner

Project description:Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs (PNETs) that correlated with high level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor suppressor pathways in the arrested cells. Specific inactivation of p53 had no effect on the RABL6A knockdown phenotype, indicating RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation restored G1 to S phase progression in RABL6A knockdown cells although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a new negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients. Total RNA obtained from human BON-1 PNET cells with RABL6A shRNA knockdown compared to BON-1 cells expressing control vector.

2014-07-01 | E-GEOD-53778 | biostudies-arrayexpress

Critical role for P53 in regulating the cell cycle of ground state embryonic stem cells [RNA-seq]

Project description:Mouse Embryonic Stem Cells (ESCs) grown in serum-supplemented conditions are characterized by an extremely short G1-phase due to the lack of G1-phase control. Concordantly, the G1-phase-specific P53-P21 pathway is compromised in serum ESCs. Here we provide evidence that P53 is activated upon transition of serum ESCs to their pluripotent ground state using serum-free 2i conditions and modulates G1-phase progression. Our data shows that the elongated G1-phase characteristic of ground state ESCs is dependent on P53. RNA-seq and ChIP-seq analyses reveal that P53 directly regulates the expression of the Retinoblastoma (RB) protein and that the hypo-phosphorylated, active RB protein plays a key role in G1-phase control. Our findings suggest that the P53-P21 pathway is active in ground state 2i ESCs and that its role in the G1-checkpoint is abolished in serum ESCs. Taken together, the data reveals a mechanism by which inactivation of P53 can lead to loss of RB and uncontrolled cell proliferation.

2019-11-30 | GSE141178 | GEO

Critical role for P53 in regulating the cell cycle of ground state embryonic stem cells [ChIP-seq]

2019-11-30 | GSE141177 | GEO

LncRNA LIMp27 regulates the DNA damage response through p27 in p53-defective cancer cells

Project description:P53 inactivation occurs in about 50% of human cancers, where p53-driven p21 activity is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, we show that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and contributes to proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasmically localized hnRNA0, which otherwise stabilizes p27 mRNA leading to cell cycle arrest at the G0/G1 phase. In response to DNA damage, LIMp27 is upregulated in both wild-type and p53-mutant COAD cells, whereas cytoplasmic hnRNPA0 is only increased in p53-mutant COAD cells due to translocation from the nucleus. Moreover, high LIMp27 expression is associated with poor survival of p53-mutant but not wild-type p53 COAD patients. These results uncover a lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers.

| MSV000090292 | MassIVE

Identification of UTP14A interactors by endogenous UTP14A IP-MS

Project description:Ribosome biogenesis is a complex and energy demanding process requiring tight coordination with cell growth and proliferation. Impairment of ribosome biogenesis activates a well-defined cell-cycle checkpoint that primarily relies on the activation of p53 signaling. However, there is mounting evidence that p53-independent signaling networks connect impaired ribosome biogenesis to cell cycle-checkpoints. So far, however, these pathways have remained largely enigmatic. By characterizing the nucleolar SUMO isopeptidase SENP3 and SENP5 we found that both isopeptidases control the SUMOylation state of specific ribosome biogenesis factors and regulate the 60S and 40S ribosome maturation pathways. Accordingly, inactivation of SENP3 and SENP5 induces a canonical p53-mediated G1/S arrest. Intriguingly, however, we discovered that inactivation of SENP3 or SENP5 drastically and specifically downregulates the expression of the key-cell cycle regulator CDK6 in a p53-independent process. Accordingly, depletion of SENP3 or SENP5 impairs G1/S transition and cell proliferation in both p53-proficient and p53-deficient cells. Strikingly, we further revealed that impaired ribosome maturation induced by depletion of a panel of ribosome biogenesis factors or by chemical inhibition of RNA polymerase I, generally triggers loss of CDK6 independent of the cellular p53 status. Altogether our data unveil a long-sought p53-independent checkpoint of impaired ribosome biogenesis. Since CDK6 represents a dependency in a subset of cancer entities, such as AML and lymphoma, we propose that this checkpoint can serve as an actionable drug target in tumor therapy.

2023-10-28 | PXD043556 | Pride

Identification of SENP3 and SENP5 target proteins by endogenous SUMO2/3 IP-MS

2023-10-28 | PXD037793 | Pride

Whole cell proteome of U2OS cells or Saos-2 cells depleted for SENP3

2023-10-28 | PXD037800 | Pride

Identification of SENP5 target proteins by endogenous SUMO2/3 IP-MS

2023-10-28 | PXD037796 | Pride

The G1 arrest and maintenance mechanism between the long-term G1-arrested and the G1-arrested cells.

Project description:Non mitotic tumor cells are resistant to conventional chemotherapeutic drugs. However, the mechanisms underlying this phenomenon remain unclear. Here, we found a population that is viable but remains in the G1 phase for an extended period of time (up to 48 h) by Long-term time-lapse observations in Fucci-HCT116 cells and then we conducted DNA microarray-based comparative analyses between the RR (the long-term G1-arrested cells) and R (the G1-arrested cells) fractions, to determine the molecular basis of the G1 arrest/maintenance mechanism. This study is related to GSE34940.

2015-01-27 | GSE61088 | GEO

Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB

Project description:Transcriptome analysis of control and MALAT1 lncRNA-depleted RNA samples from human diploid lung fibroblasts [WI38] The long noncoding MALAT1 RNA is upregulated in cancer tissues and its elevated expression is associated with hyper-proliferation, but the underlying mechanism is poorly understood. We demonstrate that MALAT1 levels are regulated during normal cell cycle progression. Genome-wide transcriptome analyses in normal human diploid fibroblasts reveal that MALAT1 modulates the expression of cell cycle genes, and is required for G1/S and mitotic progression. Depletion of MALAT1 leads to activation of p53 and its target genes. The cell cycle defects observed in MALAT1-depleted cells are sensitive to p53 levels, indicating that p53 is a major downstream mediator of MALAT1 activity. Furthermore, MALAT1-depleted cells display reduced expression of B-MYB (Mybl2), an oncogenic transcription factor involved in G2/M progression, due to altered binding of splicing factors on B-MYB pre-mRNA and aberrant alternative splicing. In human cells, MALAT1 promotes cellular proliferation by modulating the expression and/or pre-mRNA processing of cell cycle-regulated transcription factors. These findings provide mechanistic insights on the role of MALAT1 in regulating cellular proliferation. We analyzed RNA from control and MALAT1 depleted WI38 cells using the Affymetrix Human Exon 1.0 ST platform. Array data was analyzed by Partek Genomic Suite software.

2013-01-29 | E-GEOD-43830 | biostudies-arrayexpress

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