Truncation in CCND1 mRNA 3′ UTR Is Associated with An Aggressive Phenotype and Chemoresistance

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5287-5287
Author(s):  
Robert W Chen ◽  
Myo Htut ◽  
Britta Hoehn ◽  
Eamon Berge ◽  
William Robinson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Expression ◽  
Cyclin D1 ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Serum Starvation ◽  
Cycle Progression ◽  
Serum Free ◽  
Aggressive Phenotype ◽  
Free Media

Abstract Mantle Cell Lymphoma (MCL) represents 5–10% of all non-Hodgkins lymphomas, making it an uncommon but difficult form of lymphoma to treat. It has the worst prognosis among the B cell lymphomas with median survival of three years. The genetic hallmark of MCL is the t(11,14)(q13;32) translocation causing amplification of cyclin D1 (CCND1). It is a well known cell cycle regulator. Multiple reports have shown a truncation in the cyclin D1 mRNA 3′ untranslated region. This truncation increases CCND1 protein expression by not only enhancing the half-life of CCND1 mRNA, but also evades microRNA regulation of mRNA translation. The dramatic overexpression of CCND1 mRNA and protein has been associated to poor clinical outcome in patients. We hypothesize that this truncation leads to a more aggressive phenotype and induces chemoresistance in MCL. We have identified 4 MCL cell lines (Granta-519, JVM-2, Jeko-1, and Z138) with different levels of the truncated CCND1 mRNA. We were able to show that Z138 and Jeko-1 have a much higher ratio of truncated CCND1 mRNA to the full length CCND1 mRNA as compared to Granta-519 and JVM-2. We were also able to show that this truncated mRNA leads to an increase in CCND1 protein expression. By using flow cytometry, we correlated the increase in CCND1 protein expression to faster cell cycle progression. We proposed that cell lines with increased CCND1 expression are phenotypically more aggressive, and would be able to continue cell cycle progression without serum support. We were able to arrest JVM-2 in G1 phase after 48 hours of serum starvation. However, we were not able to arrest cell cycle progression in Jeko-1 even after 96 hours of serum starvation. Western blot analysis shows that CCND1 protein expression is decreased in JVM-2 but remains unchanged in Jeko-1 with serum starvation. The same phenomenon was observed in Granta-519 and Z138. The MCL cell lines (Jeko-1 and Z-138) with more CCND1 protein expression were able to continue cell cycle progression in serum free media. The MCL cell lines (JVM-2 and Granta-519) with less CCND1 protein expression were not able to continue cell cycle progression in serum free media. This shows that CCND1 overexpression is associated with a more aggressive phenotype. We then treated the 4 MCL cell lines with varying concentrations of doxorubicin, a standard anthracycline chemotherapy used in the treatment of MCL patients. We used MTS assay to assess cell proliferation after treatment with doxorubicin. We found the IC 50 (inhibitory concentration 50%) of doxorubicin in these cell lines varied from 6nM to 600nM. The cell lines (Jeko-1 and Z-138) with more CCND1 protein expression have a much higher IC 50 as compared to the cell lines (JVM-2 and Granta-519) with less CCND1 protein expression. This demonstrates that CCND1 overexpression is associated with chemoresistance. We conclude truncation in CCND1 mRNA leads to increased CCND1 protein expression and faster cell cycle progression CCND1 overexpression is associated with an aggressive phenotype CCND1 overexpression is associated with chemoresistance.

scholarly journals Interleukin-1alpha regulates G1 cell cycle progression and arrest in thyroid carcinoma cell lines NIM1 and NPA

1999 ◽  
Vol 160 (1) ◽  
pp. 67-73 ◽  
Author(s):  
K Zeki ◽  
I Morimoto ◽  
T Arao ◽  
S Eto ◽  
U Yamashita
Keyword(s):  
Cell Cycle ◽  
Thyroid Carcinoma ◽  
Protein Expression ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Carcinoma Cell ◽  
Cycle Progression ◽  
P21 Protein ◽  
Carcinoma Cell Lines ◽  
Thyroid Carcinoma Cell

This study provides the first report that the same cytokine (interleukin-1 (IL-1)) can induce opposite effects on cyclin-dependent kinases (Cdks) and Cdk inhibitors (Cdkis) in the G1 phase even in the same type of cancer cells (papillary thyroid carcinoma cells). Cell cycle analysis revealed an increase in NIM1 cells and a decrease in NPA cells in the S and G2+M phases after treatment with IL-1alpha. The addition of IL-1alpha to NIM1 cells reduced the expression of p16 and p21 protein and induced the expression of Cdk2 and Cdk4 protein, which leads to the phosphorylation of retinoblastoma protein. The addition of IL-1alpha to NPA cells induced the expression of p27 protein and reduced the expression of Cdk2 protein, which leads to induction of p107 protein expression. It is of interest that p21 protein expression was not observed in NPA cells. These results suggest that several Cdks and Cdkis play a regulatory role in the G1 cell cycle progression and arrest induced by IL-1alpha in thyroid carcinoma cell lines.

scholarly journals The RASSF1A Tumor Suppressor Blocks Cell Cycle Progression and Inhibits Cyclin D1 Accumulation

2002 ◽  
Vol 22 (12) ◽  
pp. 4309-4318 ◽  
Author(s):  
Latha Shivakumar ◽  
John Minna ◽  
Toshiyuki Sakamaki ◽  
Richard Pestell ◽  
Michael A. White
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cyclin D1 ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Phase Cell ◽  
Cycle Progression ◽  
Cycle Arrest

ABSTRACT The RASSF1A locus at 3p21.3 is epigenetically inactivated at high frequency in a variety of solid tumors. Expression of RASSF1A is sufficient to revert the tumorigenicity of human cancer cell lines. We show here that RASSF1A can induce cell cycle arrest by engaging the Rb family cell cycle checkpoint. RASSF1A inhibits accumulation of native cyclin D1, and the RASSF1A-induced cell cycle arrest can be relieved by ectopic expression of cyclin D1 or of other downstream activators of the G1/S-phase transition (cyclin A and E7). Regulation of cyclin D1 is responsive to native RASSF1A activity, because RNA interference-mediated downregulation of endogenous RASSF1A expression in human epithelial cells results in abnormal accumulation of cyclin D1 protein. Inhibition of cyclin D1 by RASSF1A occurs posttranscriptionally and is likely at the level of translational control. Rare alleles of RASSF1A, isolated from tumor cell lines, encode proteins that fail to block cyclin D1 accumulation and cell cycle progression. These results strongly suggest that RASSF1A is an important human tumor suppressor protein acting at the level of G1/S-phase cell cycle progression.

scholarly journals PARP14 regulates cyclin D1 expression to promote cell-cycle progression

Oncogene ◽  
2021 ◽  
Author(s):  
Michael J. O’Connor ◽  
Tanay Thakar ◽  
Claudia M. Nicolae ◽  
George-Lucian Moldovan
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Promote Cell Cycle Progression

scholarly journals Interleukin-2 expression in human carcinoma cell lines and its role in cell cycle progression

Oncogene ◽  
2000 ◽  
Vol 19 (4) ◽  
pp. 514-525 ◽  
Author(s):  
Torsten E Reichert ◽  
Shigeki Nagashima ◽  
Yoshiro Kashii ◽  
Joanna Stanson ◽  
Gui Gao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Carcinoma Cell ◽  
Interleukin 2 ◽  
Cycle Progression ◽  
Human Carcinoma ◽  
Carcinoma Cell Lines ◽  
Human Carcinoma Cell

scholarly journals Delayed Cell Cycle Progression and Apoptosis Induced by Hemicellulase-TreatedAgaricus blazei

2007 ◽  
Vol 4 (1) ◽  
pp. 83-94 ◽  
Author(s):  
Masaki Kawamura ◽  
Hirotake Kasai
Keyword(s):  
Cell Cycle ◽  
P38 Mapk ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Combined Treatment ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Activation Effect ◽  
Cycle Progression ◽  
Fraction H

We examined the effects of hemicellulase-treatedAgaricus blazei(AB fraction H, ABH) on growth of several tumor cell lines. ABH inhibited the proliferation of some cell lines without cytotoxic effects. It markedly prolonged the S phase of the cell cycle. ABH also induced mitochondria-mediated apoptosis in different cell lines. However, it had no impact on the growth of other cell lines. ABH induced strong activation of p38 mitogen-activated protein kinase (MAPK) in the cells in which it evoked apoptosis. On the other hand, ABH showed only a weak p38 activation effect in those cell lines in which it delayed cell cycle progression with little induction of apoptosis. However, p38 MAPK-specific inhibitor inhibited both ABH-induced effects, and ABH also caused apoptosis in the latter cells under conditions of high p38 MAPK activity induced by combined treatment with TNF-α. These results indicate that the responsiveness of p38 MAPK to ABH, which differs between cell lines, determines subsequent cellular responses on cell growth.

scholarly journals Induction of cell cycle progression by adenovirus E1A gene 13S- and 12S-mRNA products in quiescent rat cells.

1987 ◽  
Vol 7 (10) ◽  
pp. 3846-3852 ◽  
Author(s):  
T Nakajima ◽  
M Masuda-Murata ◽  
E Hara ◽  
K Oda
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Adenovirus Type ◽  
Inducible Promoter ◽  
Similar Rate ◽  
Cycle Progression ◽  
Adenovirus E1a ◽  
Tumor Virus ◽  
E1a Gene

Rat 3Y1 cell lines that express either adenovirus type 12 E1A 13S mRNA or 12S mRNA in response to dexamethasone treatment were established by introduction of recombinant vector DNA containing the E1A 13S- or 12S-mRNA cDNA placed downstream of the hormone-inducible promoter of mouse mammary tumor virus. These cell lines were growth arrested, and the induction of cell cycle progression was analyzed by flow cytometry after switch on of the cDNA by the addition of dexamethasone. The results indicate that the 13S- or 12S-mRNA product alone has the ability to cause progression of the cell cycle at a similar rate. The simultaneous addition of epidermal growth factor accelerated the rate of cell cycle progression in the transition from the G0/G1 phase to the S phase.

scholarly journals Microarray gene expression profiling in colorectal (HCT116) and hepatocellular (HepG2) carcinoma cell lines treated withMelicope ptelefolialeaf extract reveals transcriptome profiles exhibiting anticancer activity

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5203 ◽  
Author(s):  
Mohammad Faujul Kabir ◽  
Johari Mohd Ali ◽  
Onn Haji Hashim
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Replication ◽  
Cell Lines ◽  
Microarray Data ◽  
Expression Profiling ◽  
Cell Cycle Progression ◽  
Anticancer Activities ◽  
Microarray Gene Expression ◽  
Cycle Progression

BackgroundWe have previously reported anticancer activities ofMelicope ptelefolia(MP) leaf extracts on four different cancer cell lines. However, the underlying mechanisms of actions have yet to be deciphered. In the present study, the anticancer activity of MP hexane extract (MP-HX) on colorectal (HCT116) and hepatocellular carcinoma (HepG2) cell lines was characterized through microarray gene expression profiling.MethodsHCT116 and HepG2 cells were treated with MP-HX for 24 hr. Total RNA was extracted from the cells and used for transcriptome profiling using Applied Biosystem GeneChip™ Human Gene 2.0 ST Array. Gene expression data was analysed using an Applied Biosystems Expression Console and Transcriptome Analysis Console software. Pathway enrichment analyses was performed using Ingenuity Pathway Analysis (IPA) software. The microarray data was validated by profiling the expression of 17 genes through quantitative reverse transcription PCR (RT-qPCR).ResultsMP-HX induced differential expression of 1,290 and 1,325 genes in HCT116 and HepG2 cells, respectively (microarray data fold change, MA_FC ≥ ±2.0). The direction of gene expression change for the 17 genes assayed through RT-qPCR agree with the microarray data. In both cell lines, MP-HX modulated the expression of many genes in directions that support antiproliferative activity. IPA software analyses revealed MP-HX modulated canonical pathways, networks and biological processes that are associated with cell cycle, DNA replication, cellular growth and cell proliferation. In both cell lines, upregulation of genes which promote apoptosis, cell cycle arrest and growth inhibition were observed, while genes that are typically overexpressed in diverse human cancers or those that promoted cell cycle progression, DNA replication and cellular proliferation were downregulated. Some of the genes upregulated by MP-HX include pro-apoptotic genes (DDIT3, BBC3, JUN), cell cycle arresting (CDKN1A, CDKN2B), growth arrest/repair (TP53, GADD45A) and metastasis suppression (NDRG1). MP-HX downregulated the expression of genes that could promote anti-apoptotic effect, cell cycle progression, tumor development and progression, which include BIRC5, CCNA2, CCNB1, CCNB2, CCNE2, CDK1/2/6, GINS2, HELLS, MCM2/10 PLK1, RRM2 and SKP2. It is interesting to note that all six top-ranked genes proposed to be cancer-associated (PLK1, MCM2, MCM3, MCM7, MCM10 and SKP2) were downregulated by MP-HX in both cell lines.DiscussionThe present study showed that the anticancer activities of MP-HX are exerted through its actions on genes regulating apoptosis, cell proliferation, DNA replication and cell cycle progression. These findings further project the potential use of MP as a nutraceutical agent for cancer therapeutics.

scholarly journals High Mobility Group A1 Chromatin Regulators Function As Critical Drivers of Leukemogenesis in Preclinical Models of Relapsed, Pediatric B-Cell ALL

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3946-3946
Author(s):  
Liping Li ◽  
Katharina Hayer ◽  
Lingling Xian ◽  
Li Luo ◽  
Leslie Cope ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
High Mobility ◽  
Transcriptional Networks ◽  
Rna Seq ◽  
Cycle Progression ◽  
Short Hairpin ◽  
Reh Cells

Introduction: Acute B-cell lymphoblastic leukemia (B-ALL) is the most common form of childhood leukemia and the leading cause of death in children with cancer. While therapy is often curative, about 10-15% of children will relapse with recurrent disease and abysmal outcomes. Actionable mechanisms that mediate relapse remain largely unknown. The gene encoding the High Mobility Group A1(HMGA1) chromatin regulator is overexpressed in diverse malignancies where high levels portend poor outcomes. In murine models, we discovered thatHmga1 overexpression is sufficient for clonal expansion and progression to aggressive acute lymphoid leukemia (Cancer Res 2008,68:10121, 2018,78:1890; Nature Comm 2017,8:15008). Further, HMGA1 is overexpressed in pediatric B-ALL (pB-ALL) blasts with highest levels in children who relapse early compared to those who achieve chronic remissions. Together, these findings suggest that HMGA1 is required for leukemogenesis and may foster relapse in B-ALL. We therefore sought to: 1) test the hypothesis that HMGA1 is a key epigenetic regulator required for leukemogenesis and relapse in pB-ALL, and, 2) elucidate targetable mechanisms mediated by HMGA1 in leukemogenesis. Methods: We silenced HMGA1 via lentiviral delivery of short hairpin RNAs targeting 2 different sequences in cell lines derived from relapsed pB-ALL (REH, 697). REH cells harbor the TEL-AML1 fusion; 697 cells express BCL2, BCL3, and cMYC. Next, we assessed leukemogenic phenotypes in vitro (proliferation, cell cycle progression, apoptosis, and clonogenicity) and leukemogenesis invivo. To dissect molecular mechanisms underlying HMGA1, we performed RNA-Seq and applied in silico pathway analysis. Results: There is abundant HMGA1 mRNA and protein in both pB-ALL cell lines and HMGA1 was effectively silenced by short hairpin RNA. Further, silencing HMGA1 dramatically halts proliferation in both cell lines, leading to a decrease in cells in S phase with a concurrent increase in G0/S1. Apoptosis also increased by 5-10% after HMGA1 silencing based on flow cytometry for Annexin V. In colony forming assays, silencing HMGA1 impaired clonogenicity in both pB-ALL cell lines. To assess HMGA1 function in leukemogenesis in vivo, we implanted control pB-ALL cells (transduced with control lentivirus) or those with HMGA1 silencing via tail vein injection into immunosuppressed mice (NOD/SCID/IL2 receptor γ). All mice receiving control REH cells succumbed to leukemia with a median survival of only 29 days. At the time of death, mice had marked splenomegaly along with leukemic cells circulating in the peripheral blood and infiltrating both the spleen and bone marrow. In contrast, mice injected with REH cells with HMGA1 silencing survived for >40 days (P<0.001) and had a significant decrease in tumor burden in the peripheral blood, spleen, and bone marrow. Similar results were obtained with 697 cells, although this model was more fulminant with control mice surviving for a median of only 17 days. To determine whether the leukemic blasts found in mice injected with ALL cells after HMGA1 silencing represented a clone that expanded because it escaped HMGA1 silencing, we assessed HMGA1 levels and found that cells capable of establishing leukemia had high HMGA1 expression, with levels similar to those observed in control cells without HMGA1 silencing. RNA-Seq analyses from REH and 697 cell lines with and without HMGA1 silencing revealed that HMGA1 up-regulates transcriptional networks involved in RAS/MAPK/ERK signaling while repressing the IDH1 metabolic gene, the latter of which functions in DNA and histone methylation. Studies are currently underway to identify effective agents to target HMGA1 pathways. Conclusions: Silencing HMGA1 dramatically disrupts leukemogenic phenotypes in vitro and prevents the development of leukemia in mice. Mechanistically, RNA-Seq analyses revealed that HMGA amplifies transcriptional networks involved cell cycle progression and epigenetic modifications. Our findings highlight the critical role for HMGA1 as a molecular switch required for leukemic transformation in pB-ALL and a rational therapeutic target that may be particularly relevant for relapsed B-ALL. Disclosures No relevant conflicts of interest to declare.

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