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P-TEFb goes viral

Zaborowska J, Isa NF, Murphy S

Inside Cell, 2016 04;1(2):106-116.
PMID: 27398404

Positive transcription elongation factor b (P-TEFb), which comprises cyclin-dependent kinase 9 (CDK9) kinase and cyclin T subunits, is an essential kinase complex in human cells. Phosphorylation of the negative elongation factors by P-TEFb is required for productive elongation of transcription of protein-coding genes by RNA polymerase II (pol II). In addition, P-TEFb-mediated phosphorylation of the carboxyl-terminal domain (CTD) of the largest subunit of pol II mediates the recruitment of transcription and RNA processing factors during the transcription cycle. CDK9 also phosphorylates p53, a tumor suppressor that plays a central role in cellular responses to a range of stress factors. Many viral factors affect transcription by recruiting or modulating the activity of CDK9. In this review, we will focus on how the function of CDK9 is regulated by viral gene products. The central role of CDK9 in viral life cycles suggests that drugs targeting the interaction between viral products and P-TEFb could be effective anti-viral agents.

Matched MeSH terms: Genes, cdc
DNMT1 is associated with cell cycle and DNA replication gene sets in diffuse large B-cell lymphoma

Loo SK, Ab Hamid SS, Musa M, Wong KK

Pathol Res Pract, 2018 Jan;214(1):134-143.
PMID: 29137822 DOI: 10.1016/j.prp.2017.10.005

Dysregulation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) is associated with the pathogenesis of various types of cancer. It has been previously shown that DNMT1 is frequently expressed in diffuse large B-cell lymphoma (DLBCL), however its functions remain to be elucidated in the disease. In this study, we gene expression profiled (GEP) shRNA targeting DNMT1(shDNMT1)-treated germinal center B-cell-like DLBCL (GCB-DLBCL)-derived cell line (i.e. HT) compared with non-silencing shRNA (control shRNA)-treated HT cells. Independent gene set enrichment analysis (GSEA) performed using GEPs of shRNA-treated HT cells and primary GCB-DLBCL cases derived from two publicly-available datasets (i.e. GSE10846 and GSE31312) produced three separate lists of enriched gene sets for each gene sets collection from Molecular Signatures Database (MSigDB). Subsequent Venn analysis identified 268, 145 and six consensus gene sets from analyzing gene sets in C2 collection (curated gene sets), C5 sub-collection [gene sets from gene ontology (GO) biological process ontology] and Hallmark collection, respectively to be enriched in positive correlation with DNMT1 expression profiles in shRNA-treated HT cells, GSE10846 and GSE31312 datasets [false discovery rate (FDR) <0.05]. Cell cycle progression and DNA replication were among the significantly enriched biological processes (FDR <0.05). Expression of genes involved in the activation of cell cycle and DNA replication (e.g. CDK1, CCNA2, E2F2, PCNA, RFC5 and POLD3) were highly correlated (r>0.8) with DNMT1 expression and significantly downregulated (log fold-change

Matched MeSH terms: Genes, cdc
Fulltext Microarray gene expression profiling in colorectal (HCT116) and hepatocellular (HepG2) carcinoma cell lines treated with Melicope ptelefolia leaf extract reveals transcriptome profiles exhibiting anticancer activity

Kabir MF, Mohd Ali J, Haji Hashim O

PeerJ, 2018;6:e5203.
PMID: 30042885 DOI: 10.7717/peerj.5203

Background: We have previously reported anticancer activities of Melicope 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.
Methods: HCT116 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).
Results: MP-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.
Discussion: The 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.

Matched MeSH terms: Genes, cdc
Fulltext Effect of perivitelline fluid from horseshoe crab on the expression of cell cycle regulatory genes in human dental pulp stem cells

Abdul Qawee Rani, Thirumulu Ponnuraj Kannan, Nur Izyan Azmi, Najian Binti Ibrahim, Nor Shamsuria Omar, Ahmad Azlina, et al.

Archives of Orofacial Sciences, 2016;11(1):7-14.
MyJurnal

Perivitelline fluid (PVF) of the horseshoe crab embryo has been reported to possess an important role
during embryogenesis by promoting cell proliferation. This study aims to evaluate the effect of PVF on the
expression of cell cycle regulatory genes from human dental pulp stem cells (DPSCs) between different cell
passages viz. 4, 5, 6. The cells were treated with a single dose of PVF (26.89 mg/ml) PVF. Gene expression was
quantified for CDKNA2A, PTEN, MDM2 and TP53 genes using reverse transcriptase PCR. CDKN2A and MDM2
expression for treated and untreated DPSCs, expressed a similar pattern of expression. The higher expression of
CDKN2A showed that the treatment increased cell proliferation and prevented cell senescence. DPSCs with PVF
treatment showed increased expression of MDM2 at passage 4 and drastically declined expression at passage 5
and slightly increased at passage 6. TP53 expression of DPSCs treated group showed a higher expression
compared to untreated group. On the other hand, the expression of PTEN in DPSCs treated group started to
increase from passage 5 to 6. However, on the whole, the PTEN expression was higher than the untreated group
in all the passages studied here. The results showed that PVF could enhance cell cycle regulatory gene
expression in DPSCs as indicated by the higher expression of all the genes considered in this study at different
cell passages in the treated group compared to the untreated group. Mann Whitney test was utilized to determine
the significance of cell cycle regulatory genes expression between treated and untreated group. Significant
difference in expression of genes between the treated and untreated groups were found at all passages except
for CDKN2A gene whereby, its expression was not significantly different at passage 5 though it did express
slightly higher in PVF treated DPSCs.

Matched MeSH terms: Genes, cdc
Fulltext Microarray analysis revealed different gene expression patterns in HepG2 cells treated with low and high concentrations of the extracts of Anacardium occidentale shoots

Khaleghi S, Aziz AA, Razali N, Junit SM

Genes Nutr, 2011 Nov;6(4):413-27.
PMID: 21484159 DOI: 10.1007/s12263-011-0216-z

In this study, the effects of low and high concentrations of the Anacardium occidentale shoot extracts on gene expression in liver HepG2 cells were investigated. From MTT assays, the concentration of the shoot extracts that maintained 50% cell viability (IC(50)) was 1.7 mg/ml. Cell viability was kept above 90% at both 0.4 mg/ml and 0.6 mg/ml of the extracts. The three concentrations were subsequently used for the gene expression analysis using Affymetrix Human Genome 1.0 S.T arrays. The microarray data were validated using real-time qRT-PCR. A total of 246, 696 and 4503 genes were significantly regulated (P

Matched MeSH terms: Genes, cdc
The current status of checkpoint inhibitors in metastatic bladder cancer

Fahmy O, Khairul-Asri MG, Stenzl A, Gakis G

Clin Exp Metastasis, 2016 Oct;33(7):629-35.
PMID: 27380916 DOI: 10.1007/s10585-016-9807-9

For many decades, no significant improvements could be achieved to prolong the survival in metastatic bladder cancer. Recently, systemic immunotherapy with checkpoint inhibitors (anti-PD-L1/anti-CTLA-4) has been introduced as a novel treatment modality for patients with metastatic bladder cancer. We conducted a systematic review according to the PRISMA statement for data published on the clinical efficacy of checkpoint inhibitors in metastatic bladder cancer. Clinical efficacy of anti PD-L1 therapy was investigated in prospective trials in a total of 155 patients. Patients with positive expression for PD-L1 tended towards better overall response rates (ORR) compared to those with negative expression (34/76 vs 10/73, 45 vs 14 %; p = 0.21). Among patients with PD-L1 positive tumors, those with non-visceral metastases exhibited significantly higher ORR compared to those with visceral metastases (82 vs 28 %; p = 0.001). For anti-CTLA4 therapy, there were no data retrievable on clinical efficacy. Although data on clinical efficacy of checkpoint inhibitors in metastatic bladder cancer are currently limited, the efficacy of these drugs might depend mainly on the metastatic volume and immune system integrity. Patients with PD-L1 positive tumors and non-visceral metastases seem to derive the highest benefit from therapy.

Matched MeSH terms: Genes, cdc/drug effects
A B-myb--DREAM complex is not critical to regulate the G2/M genes in HPV-transformed cell lines

Rashid NN, Yusof R, Watson RJ

Anticancer Res, 2014 Nov;34(11):6557-63.
PMID: 25368258

It is well-established that HPV E7 proteins, encoded by human papillomavirus (HPV) genes, frequently associated with cervical cancers bind avidly to the retinoblastoma (RB) family of pocket proteins and disrupt their association with members of the E2F transcription factor family. Our previous study showed that the repressive p130-dimerization partner, RB-like, E2F and multi-vulval class (DREAM) complex was disrupted by HPV16 E7 proteins in order to maintain the viral replication in CaSki cells. However, we would like to address whether the activator B-myb-DREAM complex is critical in regulating the replication and mitosis phase since our previous study showed increased B-myb-DREAM expression in HPV-transformed cell lines when compared to control cells.

Matched MeSH terms: Genes, cdc/physiology*