The role of cyclin-dependent kinase inhibitor 3 in the proliferation and migration of renal cell carcinoma.

The cyclin-dependent kinase inhibitor 3 (CDKN3) gene, is over expressed in renal cell carcinoma (RCC). However, the cell biology functions of RCC are not well understood. The present study aimed to verify the ability of CDKN3 to promote the proliferation and migration of RCC through in vitro experiments. Subsequently, the clinical prognostic effects were analyzed using The Cancer Genome Atlas (TCGA; https://www.cancer.gov/) and Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/). The chelators, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), an analogue of the anti-tumor agent, were screened through bioinformatics analysis. The expression of CDKN3 is positively correlated with the IC50 of Dp44mT. In two RCC cell lines, 786-0 and Caki-1, we conducted small interfering RNA (siRNA) knockdown of CDKN3 and overexpression of CDKN3 by transfection plasmid. Subsequently, we administered Dp44mT to examine the resulting alterations in cell proliferation, migration, and apoptosis, thereby elucidating the role of CDKN3 and Dp44mT in these processes. The results of the experiment revealed a positive association between CDKN3 expression and the proliferation of RCC cell lines. Down-regulating CDKN3 significantly increased the apoptosis rate and inhibited cell migration in 786-0 and Caki-1 cells. Furthermore, bioinformatics analysis revealed a high expression of CDKN3 in RCC and a negative association between CDKN3 expression and survival. Gene set enrichment analysis (GSEA) revealed a significant association between high CDKN3 expression and the cell cycle pathway. Furthermore, we identified Dp44mT as a drug highly correlated with CDKN3 through the database. Subsequent addition of Dp44mT resulted in similar findings to those observed upon CDKN3 knockdown. Our findings have important implications for the diagnosis and treatment of CDKN3 in RCC. Additionally, Dp44mT is likely to be a promising candidate for future clinical applications.

N6-Methyladenosine modified circ-NAB1 modulates cell cycle and epithelial-mesenchymal transition via CDKN3 in endometrial cancer.

Endometrial cancer (EC) is a common malignant tumor in the female reproductive system. Circular RNAs (circRNAs) and N6-methyladenosine (m6A) modification are widely involved in cancer progression. Nevertheless, the cross-talk between circ-NAB1 and m6A as well as the biological functions of circ-NAB1 in EC remain unclear. Circ-NAB1 was observed to be upregulated in EC tissues and cells by RT-qPCR. MeRIP and RNA pull-down assays were utilized for detecting the m6A modification of circ-NAB1. The interaction between circ-NAB1 and RNAs was also detected. Colony formation, transwell, flow cytometry, and western blot were utilized for measuring EC cell behaviors. Mechanically, we proved the m6A demethylase alkylation repair homolog protein 5 (ALKBH5) can mediate circ-NAB1 expression through an m6A-YTHDF2-dependent manner. Circ-NAB1 overexpression can promote cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT) process, and cell cycle through functional assays. Circ-NAB1 knockdown exerts the opposite function on EC cells. Furthermore, we proved that circ-NAB1 can sponge miR-876-3p to upregulate the target gene cyclin-dependent kinase inhibitor 3 (CDKN3) in EC cells. CDKN3 overexpression can reverse the impacts of circ-NAB1 depletion on EC cell behaviors. Collectively, we proved that ALKBH5-mediated m6A modification of circ-NAB1 promoted EMT process and cell cycle in EC via targeting the miR-876-3p/CDKN3 axis.

Human pan-cancer analysis of the predictive biomarker for the CDKN3.

BACKGROUND: Cell cycle protein-dependent kinase inhibitor protein 3 (CDKN3), as a member of the protein kinase family, has been demonstrated to exhibit oncogenic properties in several tumors. However, there are no pan-carcinogenic analyses for CDKN3. METHODS: Using bioinformatics tools such as The Cancer Genome Atlas (TCGA) and the UCSC Xena database, a comprehensive pan-cancer analysis of CDKN3 was conducted. The inverstigation encompassed the examination of CDKN3 function actoss 33 different kinds of tumors, as well as the exploration of gene expressions, survival prognosis status, clinical significance, DNA methylation, immune infiltration, and associated signal pathways. RESULTS: CDKN3 was significantly upregulated in most of tumors and correlated with overall survival (OS) of patients. Methylation levels of CDKN3 differed significantly between tumors and normal tissues. In addition, infiltration of CD4 + T cells, cancer-associated fibroblasts, macrophages, and endothelial cells were associated with CDKN3 expression in various tumors. Mechanistically, CDKN3 was associated with P53, PI3K-AKT, cell cycle checkpoints, mitotic spindle checkpoint, and chromosome maintenance. CONCLUSION: Our pan-cancer analysis conducted in the study provides a comprehensive understanding of the involvement of CDKN3 gene in tumorigenesis. The findings suggest that targeting CDKN3 may potentially lead to novel therapeutic strategies for the treatment of tumors.

Identification of short protein-destabilizing sequences in Arabidopsis cyclin-dependent kinase inhibitors, ICKs.

Plants have a family of cyclin-dependent kinase (CDK) inhibitors called interactors/inhibitors of CDK (ICKs) or Kip-related proteins (KRPs). ICK proteins have important functions in cell proliferation, endoreduplication, plant growth, and reproductive development, and their functions depend on the protein levels. However, understanding of how ICK protein levels are regulated is very limited. We fused Arabidopsis ICK sequences to green fluorescent protein (GFP) and determined their effects on the fusion proteins in plants, yeast, and Escherichia coli. The N-terminal regions of ICKs drastically reduced GFP fusion protein levels in Arabidopsis plants. A number of short sequences of 10-20 residues were found to decrease GFP fusion protein levels when fused at the N-terminus or C-terminus. Three of the four short sequences from ICK3 showed a similar function in yeast. Intriguingly, three short sequences from ICK1 and ICK3 caused the degradation of the fusion proteins in E. coli. In addition, computational analyses showed that ICK proteins were mostly disordered and unstructured except for the conserved C-terminal region, suggesting that ICKs are intrinsically disordered proteins. This study has identified a number of short protein-destabilizing sequences, and evidence suggests that some of them may cause protein degradation through structural disorder and instability.

Application of novel PACS-based informatics platform to identify imaging based predictors of CDKN2A allelic status in glioblastomas.

Gliomas with CDKN2A mutations are known to have worse prognosis but imaging features of these gliomas are unknown. Our goal is to identify CDKN2A specific qualitative imaging biomarkers in glioblastomas using a new informatics workflow that enables rapid analysis of qualitative imaging features with Visually AcceSAble Rembrandtr Images (VASARI) for large datasets in PACS. Sixty nine patients undergoing GBM resection with CDKN2A status determined by whole-exome sequencing were included. GBMs on magnetic resonance images were automatically 3D segmented using deep learning algorithms incorporated within PACS. VASARI features were assessed using FHIR forms integrated within PACS. GBMs without CDKN2A alterations were significantly larger (64 vs. 30%, p = 0.007) compared to tumors with homozygous deletion (HOMDEL) and heterozygous loss (HETLOSS). Lesions larger than 8 cm were four times more likely to have no CDKN2A alteration (OR: 4.3; 95% CI 1.5-12.1; p < 0.001). We developed a novel integrated PACS informatics platform for the assessment of GBM molecular subtypes and show that tumors with HOMDEL are more likely to have radiographic evidence of pial invasion and less likely to have deep white matter invasion or subependymal invasion. These imaging features may allow noninvasive identification of CDKN2A allele status.

RNAseq analysis of mutants in coding and non-coding transcription of phosphate genes in the yeast Saccharomyces cerevisiae.

In the yeast Saccharomyces cerevisiae phosphate starvation induces the expression of PHO genes, including PHO84, encoding an high-affinity phosphate transporter, and SPL2, encoding a regulatory protein. PHO84 is down-regulated by antisense transcription. Here, using strand-specific RNAseq the effect is studied of mutations related to sense and antisense transcription of phosphate genes. Replacement of the transcriptional terminator of PHO84 by that of CYC1 resulted, unexpectedly, in an increased antisense transcription and a strongly reduced sense transcription of PHO84 and a strongly reduced SPL2 expression. The expression of unrelated genes was altered as well. The data suggest that antisense transcription of PHO84 and not the Pho84 transporter affects the expression of SPL2. Deletion of the two putative binding sites for Ume6 in the SPL2 promoter or deletion of UME6 differently affected SPL2 expression, suggesting that Ume6 regulates SPL2 by a mechanism different from a simple binding to the putative Ume6 binding sites.

Isolation and characterization of the gene HvFAR1 encoding acyl-CoA reductase from the cer-za.227 mutant of barley (Hordeum vulgare) and analysis of the cuticular barrier functions.

The cuticle is a protective layer covering aerial plant organs. We studied the function of waxes for the establishment of the cuticular barrier in barley (Hordeum vulgare). The barley eceriferum mutants cer-za.227 and cer-ye.267 display reduced wax loads, but the genes affected, and the consequences of the wax changes for the barrier function remained unknown. Cuticular waxes and permeabilities were measured in cer-za.227 and cer-ye.267. The mutant loci were isolated by bulked segregant RNA sequencing. New cer-za alleles were generated by genome editing. The CER-ZA protein was characterized after expression in yeast and Arabidopsis cer4-3. Cer-za.227 carries a mutation in HORVU5Hr1G089230 encoding acyl-CoA reductase (FAR1). The cer-ye.267 mutation is located to HORVU4Hr1G063420 encoding ß-ketoacyl-CoA synthase (KAS1) and is allelic to cer-zh.54. The amounts of intracuticular waxes were strongly decreased in cer-ye.267. The cuticular water loss and permeability of cer-za.227 were similar to wild-type (WT), but were increased in cer-ye.267. Removal of epicuticular waxes revealed that intracuticular, but not epicuticular waxes are required to regulate cuticular transpiration. The differential decrease in intracuticular waxes between cer-za.227 and cer-ye.267, and the removal of epicuticular waxes indicate that the cuticular barrier function mostly depends on the presence of intracuticular waxes.

PSMD12 interacts with CDKN3 and facilitates pancreatic cancer progression.

Proteasome 26S subunit, non-ATPase 12 (PSMD12) genes have been implicated in several types of malignancies but the role of PSMD12 in pancreatic cancer (PC) remains elusive. Bioinformatics analysis showed that PSMD12 was highly expressed in PC patients and was associated with shorter overall survival. PSMD12 was also shown to be highly expressed in PC tissues and cell lines. Upregulated PSMD12 showed enhanced cell viability, increased colony formation rate and upregulated levels of PCNA and c-Myc, while the inhibition of PSMD12 abated these levels. PSMD12 knockdown promoted cell apoptosis. The results of xenografts in nude mice confirmed that PSMD12 promoted PC tumor growth in vivo. Protein‒protein interaction network and functional enrichment analyses implied that PSMD12 may have a connection with cyclin-dependent kinase inhibitor 3 (CDKN3). Co­immunoprecipitation and western blot results confirmed that PSMD12 could interact with and abate the ubiquitination level of CDKN3, thus stabilizing the CDKN3 protein. Rescue assays showed that PSMD12 overexpression caused cell proliferation and that knockdown-induced cell apoptosis could be reversed by CDKN3 regulation. This work reveals the essential roles of PSMD12 in the proliferation and apoptosis of PC development. PSMD12 may regulate CDKN3 expression by interacting with and abating the ubiquitination level of CDKN3, thereby participating in the malignant behavior of PC.

The cell senescence regulator p16 is a promising cancer prognostic and immune check-point inhibitor (ICI) therapy biomarker.

Cyclin-dependent kinase inhibitor 2A (CDKN2A) encodes the cell senescence regulator protein p16. The expression of p16 raises in cell senescence and has a nuclear regulation in cell aging. Meanwhile, it's also reported to inhibit the aggression of several cancers. But its clinical application and role in cancer immunotherapy needs further investigation. We collected the transcriptional data of pan-cancer and normal human tissues from The Cancer Genome Atlas and the Genotype-Tissue Expression databases. CBioPortal webtool was employed to mine the genomic alteration status of CDKN2A across cancers. Kaplan-Meier method and univariate Cox regression were performed for prognostic assessments across cancers, respectively. Gene Set Enrichment Analysis is the main method used to search the associated cancer hallmarks associated with CDKN2A. TIMER2.0 was used to analyze the immune cell infiltration relevance with CDKN2A in pan-cancer. The associations between CDKN2A and immunotherapy biomarkers or regulators were performed by spearman correlation analysis. We found CDKN2A is overexpressed in most cancers and exhibits prognosis predictive ability in various cancers. In addition, it is significantly correlated with immune-activated hallmarks, cancer immune cell infiltrations and immunoregulators. The most interesting finding is that CDKN2A can significantly predict anti-PDL1 therapy response. Finally, specific inhibitors which correlated with CDKN2A expression in different cancer types were also screened by using Connectivity Map (CMap) tool. The results revealed that CDKN2A acts as a robust cancer prognostic and immunotherapy biomarker. Its function in the regulation of cancer cell senescence might shape the tumor microenvironment and contribute to its predictive ability of immunotherapy.

GID2 Interacts With CDKN3 and Regulates Pancreatic Cancer Growth and Apoptosis.

Dysregulation of deubiquitinase or ubiquitinase-mediated protein expression contributes to various diseases, including cancer. In the present study, we identified GID2, a subunit of the glucose-induced degradation-deficient (GID) complex that functions as an E3 ubiquitin ligase, as a potential key candidate gene in pancreatic cancer (PC) progression. The functional role and potential mechanism of GID2 in PC progression were investigated. Integrated bioinformatics analysis was performed to identify differentially expressed genes in PC based on the Gene Expression Profiling Interactive Analysis data sets. We found that GID2 was upregulated in PC tissues and that a high level of GID2 expression in clinical PC samples was positively associated with tumor stage and poor survival. Functional assays elucidated that GID2 expression promoted cell growth in vitro and accelerated tumor growth in vivo. GID2 knockdown effectively attenuated the malignant behaviors of PC cells and tumor formation. Furthermore, the protein network that interacted with the GID2 protein was constructed based on the GeneMANIA website. Cyclin-dependent kinase inhibitor 3 (CDKN3), a cell cycle regulator, was identified as a potential target of the GID2 protein. We revealed that GID2 positively regulated CDKN3 expression and inhibited CDKN3 ubiquitination. Furthermore, CDKN3 downregulation reversed the promoting effects of GID2 on PC progression. Therefore, the present study demonstrated that GID2 might regulate PC progression by maintaining the stability of the CDKN3 protein. These findings highlight the potential roles of the GID2/CDKN3 axis as a potential therapeutic target in PC.

Gene-Level Associations in Patients With and Without Pathogenic Germline Variants in CDKN2A and Pancreatic Cancer.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) in CDKN2A. However, it is unclear what role this gene or other genes play in its etiology. MATERIALS AND METHODS: We analyzed 189 cancer predisposition genes using parametric rare-variant association (RVA) tests and nonparametric permutation tests to identify gene-level associations in PDAC for patients with (CDKN2A+) and without (CDKN2A-) GPV. Exome sequencing was performed on 84 patients with PDAC, 47 CDKN2A+ and 37 CDKN2A-. After variant filtering, various RVA tests and permutation tests were run separately by CDKN2A status. Genes with the strongest nominal associations were evaluated in patients with PDAC from The Cancer Genome Atlas and the UK Biobank (UKB). A secondary analysis including only GPV from UKB was also performed. RESULTS: In RVA tests, ERCC4 and RET showed the most compelling evidence as plausible PDAC candidate genes for CDKN2A+ patients. In contrast, the findings in CDKN2A- patients provided evidence for HMBS, EPCAM, and MRE11 as potential new candidate genes and confirmed ATM, BRCA2, and PALB2 as PDAC genes, consistent with findings in The Cancer Genome Atlas and the UKB. As expected, CDKN2A- patients were more likely to harbor GPVs from the 189 genes investigated. When including only GPVs from UKB, significant associations with PDAC were seen for ATM, BRCA2, and CDKN2A. CONCLUSION: These results suggest that variants in other genes likely play a role in PDAC in all patients and that PDAC in CDKN2A+ patients has a distinct etiology from PDAC in CDKN2A- patients.

INK4 cyclin-dependent kinase inhibitors as potential prognostic biomarkers and therapeutic targets in hepatocellular carcinoma.

The INK4 family is an important family of cyclin-dependent kinase inhibitors (CDKIs) and consists of CDKN2A, CDKN2B, CDKN2, and CDKN2D. Abnormal expression of CDKN2A has been reported in hepatocellular carcinoma (HCC) and is associated with the prognosis of patients and infiltration of immune cells. However, there is a lack of systematic research on the roles of the other INK4 family members in the diagnosis, prognosis, and immune regulation of HCC. Using online public databases and clinical samples, we comprehensively analyzed the INK4 family in HCC. All four INK4 proteins were overexpressed in HCC and correlated with advanced cancer stage and poor prognosis. INK4 expression accurately distinguished tumor from normal tissue, particularly CDKN2A and CDKN2C. The INK4 family participated in cell-cycle regulation and the DNA damage repair pathway, which inhibited genotoxic-induced apoptosis in tumorigenesis. INK4 proteins were positively correlated with the infiltration of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells) and immune checkpoints (CTLA-4, PD1, and PD-L1). CDKN2D had the highest correlation (correlation coefficient >0.3) with all the above-mentioned infiltrating immune cells and immune checkpoints, indicating that it may be useful as an immunotherapy target. The INK4 family was valuable for diagnosis and predicting the prognosis of HCC and participated in the occurrence, progression, and immune regulation of HCC, demonstrating its potential as a diagnostic and prognostic biomarker and therapeutic target in HCC.

The MDM2 and CDKN2A Copy-number-variation Influence the TP53-signature-score in Wild-type TP53 Luminal Type Breast Cancer.

BACKGROUND/AIM: The TP53-signature is a multi-gene signature that can predict TP53 structural mutations. It has presented remarkable ability to predict the prognosis of early-stage breast cancer. However, some samples presented discordance with the signature status and structure status. We aimed to investigate whether the mRNA expression levels or copy number variation (CNV) of MDM2 and CDKN2A influence the TP53-signature-score, subtype classification, and prognosis prediction in TP53 wild-type, luminal type early-stage breast cancer samples. MATERIALS AND METHODS: We selected TP53 wild-type, luminal type early-stage breast cancer samples from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts. Then, we analyzed the correlation between the TP53-signature-score and mRNA expression levels or CNV of MDM2 and CDKN2A. RESULTS: The samples with MDM2 copy number (CN) amplification or those with CDKN2A CN deep deletion presented higher TP53-signature-score. Moreover, samples with MDM2 CN amplification or those with CDKN2A CN deep deletion had more characteristics of the luminal B type. In addition, they showed lower estrogen response early score, which correlated with response to endocrine therapy in breast cancer. However, MDM2 and CDKN2A mRNA expression did not present the same tendency. Furthermore, samples with MDM2 CN amplification or those with CDKN2A CN deep deletion had a worse prognosis in METABRIC cohort. CONCLUSION: The MDM2 or CDKN2A CNV may be useful for classifying subtypes and predicting prognosis more accurately in TP53 wild-type, luminal type early-stage breast cancer patients.

Evaluation of gene expression of PLEKHS1, AADAC, and CDKN3 as novel genomic markers in gastric carcinoma.

Gastric cancer (GC) is considered lethal aggressive cancer. In Egypt, GC has a low incidence but unfortunately, it is mostly diagnosed at an advanced stage with a poor prognosis. Assessment of novel markers that can be used in the early detection of GC is an urgent need. The present study was performed to assess the association of the Pleckstrin homology domain-containing S1 (PLEKHS1)، arylacetamide deacetylase (AADAC, and Cyclin-dependent kinase inhibitor 3 (CDKN3) genes with GC and to correlate their gene expression levels with tumor stage, grade, and other clinicopathological features. The current work was performed on forty gastric tissue samples; twenty in Group 1 with GC tissues at different stages, and grades and twenty in Group 2 (control group) with non-tumorous tissue. PLEKHS1, AADAC, and CDKN3 gene expression were assessed by RT-qPCR. AADAC, CDKN3 genes were significantly (p<0.001) upregulated, while PLEKHS1 gene was significantly (p<0.001) downregulated in the GC group than the control group. AADAC gene expression exhibited a high significant (p<0.001) positive correlation with the tumor grades and the tumor stages. A high significant negative correlation between AADAC, and CDKN3 gene expression (r = -.760, p<0.001) was found. The three studied parameters showed high significant sensitivity and specificity in the prediction of the presence of GC. PLEKHS1, AADAC, and CDKN3 gene expressions were suggested to be used as diagnostic and predictive biomarkers of GC, additionally, AADAC may be used as a prognostic marker in these patients for further future confirming studies.

Synthetic lethality of cyclin-dependent kinase inhibitor Dinaciclib with VHL-deficiency allows for selective targeting of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (CC-RCC) remains one of the most deadly forms of kidney cancer despite recent advancements in targeted therapeutics, including tyrosine kinase and immune checkpoint inhibitors. Unfortunately, these therapies have not been able to show better than a 16% complete response rate. In this study we evaluated a cyclin-dependent kinase inhibitor, Dinaciclib, as a potential new targeted therapeutic for CC-RCC. In vitro, Dinaciclib showed anti-proliferative and pro-apoptotic effects on CC-RCC cell lines in Cell Titer Glo, Crystal Violet, FACS-based cell cycle analysis, and TUNEL assays. Additionally, these responses were accompanied by a reduction in phospho-Rb and pro-survival MCL-1 cell signaling responses, as well as the induction of caspase 3 and PARP cleavage. In vivo, Dinaciclib efficiently inhibited primary tumor growth in an orthotopic, patient-derived xenograft-based CC-RCC mouse model. Importantly, Dinaciclib targeted both CD105+ cancer stem cells (CSCs) and CD105- non-CSCs in vivo. Moreover, normal cell lines, as well as a CC-RCC cell line with re-expressed von-Hippel Lindau (VHL) tumor suppressor gene, were protected from Dinaciclib-induced cytotoxicity when not actively dividing, indicating an effective therapeutic window due to synthetic lethality of Dinaciclib treatment with VHL loss. Thus, Dinaciclib represents a novel potential therapeutic for CC-RCC.

Kel1 is a phosphorylation-regulated noise suppressor of the pheromone signaling pathway.

Mechanisms have evolved that allow cells to detect signals and generate an appropriate response. The accuracy of these responses relies on the ability of cells to discriminate between signal and noise. How cells filter noise in signaling pathways is not well understood. Here, we analyze noise suppression in the yeast pheromone signaling pathway and show that the poorly characterized protein Kel1 serves as a major noise suppressor and prevents cell death. At the molecular level, Kel1 prevents spontaneous activation of the pheromone response by inhibiting membrane recruitment of Ste5 and Far1. Only a hypophosphorylated form of Kel1 suppresses signaling, reduces noise, and prevents pheromone-associated cell death, and our data indicate that the MAPK Fus3 contributes to Kel1 phosphorylation. Taken together, Kel1 serves as a phospho-regulated suppressor of the pheromone pathway to reduce noise, inhibit spontaneous activation of the pathway, regulate mating efficiency, and prevent pheromone-associated cell death.

OIP5-AS1 Promotes Proliferation of Non-small-cell Lung Cancer and Head and Neck Squamous Cell Carcinoma Cells.

BACKGROUND/AIM: The long noncoding RNA OIP5 antisense RNA 1 (OIP5-AS1) is overexpressed in various cancer types, such as lung cancer, hepatoblastoma and cervical cancer, and functions to accelerate cell proliferation, invasion and migration. Here, we investigated the roIe of OIP5-AS1 in cell-cycle progression of H1299 and A549 non-small cell lung cancer cells, and FaDu and CAL27 head and neck squamous cell carcinoma cells. MATERIALS AND METHODS: The cells were transfected with small interfering RNA and subjected to cell-cycle analysis and reverse-transcription quantitative polymerase chain reaction (RT-qPCR). RESULTS: Silencing of OIP5-AS1 suppressed the proliferation of H1299, A549, FaDu and CAL27 cells. RT-qPCR and cell-cycle analysis revealed that silencing OIP5-AS1 increased the expression of CDK inhibitors, such as p15, p16, p18 and p19, resulting in G1-phase arrest. CONCLUSION: OIP5-AS1 regulates G1-phase progression by repressing CDK inhibitors and, thus, promotes the proliferation of H1299, A549, FaDu and CAL27 cells.

Cell size controlled in plants using DNA content as an internal scale.

How eukaryotic cells assess and maintain sizes specific for their species and cell type remains unclear. We show that in the Arabidopsis shoot stem cell niche, cell size variability caused by asymmetric divisions is corrected by adjusting the growth period before DNA synthesis. KIP-related protein 4 (KRP4) inhibits progression to DNA synthesis and associates with mitotic chromosomes. The F BOX-LIKE 17 (FBL17) protein removes excess KRP4. Consequently, daughter cells are born with comparable amounts of KRP4. Inhibitor dilution models predicted that KRP4 inherited through chromatin would robustly regulate size, whereas inheritance of excess free KRP4 would disrupt size homeostasis, as confirmed by mutant analyses. We propose that a cell cycle regulator, stabilized by association with mitotic chromosomes, reads DNA content as a cell size-independent scale.

Integrated transcriptomics explored the cancer-promoting genes CDKN3 in esophageal squamous cell cancer.

BACKGROUND AND OBJECTIVES: Each individual studies is limited to multi-factors and potentially lead to a significant difference of results among them. The present study aim to explore the critical genes related to the development of Esophageal squamous cell carcinoma (ESCC) by integrated transcriptomics and to investigate the clinical significance by experimental validation. METHODS: Datasets of protein-coding genes expression which involved in ESCC were downloaded from Gene Expression Omnibus (GEO) database. The "Robustrankaggreg" package in language was used for data integration, and the different expression genes (DEGs) were identified based the cut-off criteria as follows: adjust p-value < 0.05, |fold change (FC)| ≥ 1.5; The protein expression of seed gene in 184 cases of primary ESCC tissues and 50 tumor adjacent normal tissues (at least 5 cm away from the tumor, and defind as the controls) were detected by immunohistochemistry; The relationship between the expression level of seed genes and clinical parameter were analyze. Enumeration data were represented by frequency or percentage (%) and were tested by x2 test. The P value of less than 0.05 was considered statistically significant. RESULTS: A total of 244 DEGs were identified by comparing gene expression patterns between ESCC patients and the controls based on integrating dataset of GSE77861, GSE77861, GSE100942, GSE26886, GSE17351, GSE38129, GSE33426, GSE20347 and GSE23400; The Cyclin-dependent kinase inhibitor 3 (CDKN3) were identified the top 1 seed gene of top cluster by use of protein-protein Interaction network and plug-in Molecular Complex Detection; The level of CDKN3 mRNA was significantly increased in ESCC patients compared to controls; The positive expression rate of CDKN3 protein in ESCC tissue samples was 32 and 61.4% in control, respectively. The correlations between the expression level of CDKN3 and lymph node metastasis or clinical staging of ESCC patients are statistically significant. CONCLUSION: Integrated transcriptomics is an efficient approach to system biology. By this procedure, our study improved the understanding of the transcriptome status of ESCC.

Cell-to-cell heterogeneity of phosphate gene expression in yeast is controlled by alternative transcription, 14-3-3 and Spl2.

Dependent on phosphate availability the yeast Saccharomyces cerevisiae expresses either low or high affinity phosphate transporters. In the presence of phosphate yeast cells still express low levels of the high affinity phosphate transporter Pho84. The regulator Spl2 is expressed in approximately 90% of the cells, and is not expressed in the remaining cells. Here we report that deletion of RRP6, encoding an exonuclease degrading non-coding RNA, or BMH1, encoding the major 14-3-3 isoform, resulted in less cells expressing SPL2 and in increased levels of RNA transcribed from sequences upstream of the SPL2 coding region. SPL2 stimulates its own expression and that of PHO84 ensuing a positive feedback. Upon deletion of the region responsible for upstream SPL2 transcription almost all cells express SPL2. These results indicate that the cell-to-cell variation in PHO84 and SPL2 expression is dependent on a specific part of the SPL2 promoter and is controlled by Bmh1 and Spl2.