• ApoA-I(Milano)
• High-density lipoproteins
• LPS
• Sepsis
• Toll-like receptor

• Activating transcription factor 3
• Collagen
• Fibroblast
• Skin wound healing
• TGF-β receptor Ⅱ

• Activating Transcription Factor 3/metabolism
• Activating Transcription Factor 3/genetics
• Wound Healing/genetics
• Fibroblasts/metabolism
• Animals
• Collagen/metabolism
• Skin/metabolism
• Skin/injuries
• Skin/pathology
• Mice
• Humans
• Receptor, Transforming Growth Factor-beta Type II/metabolism
• Receptor, Transforming Growth Factor-beta Type II/genetics
• Promoter Regions, Genetic
• Male
• Transcriptional Activation
• Signal Transduction
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Hypoxia-Inducible Factor 1, alpha Subunit/genetics
• Transcription, Genetic

• CSB
• DNA repair
• Live cell imaging
• TC-NER

• DNA Repair
• DNA Damage
• Cell Line
• Chromatin
• Mass Spectrometry

Circular RNAs (circRNAs) can act as key regulators in human cancers, including esophageal squamous cell carcinoma (ESCC). However, the role and mechanism of circ_0005231 in ESCC have not previously been reported.

RNA levels and protein levels were detected by real‐time quantitative polymerase chain reaction (RT‐qPCR) and Western blot assay, respectively. Cell proliferation was assessed by colony formation assay and 5‐ethynyl‐2'‐deoxyuridine (EdU) assay. Wound healing and transwell assays were used to assess cell migration and invasion, respectively. The intermolecular interaction was predicted by bioinformatic analysis and verified by RNA immunoprecipitation (RIP), RNA pulldown and dual‐luciferase reporter assays. Xenograft tumor model was used for exploring the biological function of circ_0005231 in vivo.

Circ_0005231 was upregulated in ESCC plasma, tissues and cells. Cell proliferation, migration and invasion were significantly restrained by knockdown of circ_0005231 in ESCC cells. Circ_0005231 acted as a sponge of miR‐383‐5p, and circ_0005231 regulated ESCC cellular behavior by sponging miR‐383‐5p. Moreover, miR‐383‐5p directly targeted KIAA0101, and circ_0005231 positively regulated KIAA0101 expression by sponging miR‐383‐5p. Furthermore, circ_0005231 knockdown suppressed the malignant behavior of ESCC cells by downregulating KIAA0101. Importantly, knockdown of circ_0005231 blocked xenograft tumor growth in vivo.

Circ_0005231 acted as a sponge of miR‐383‐5p to promote ESCC progression by upregulating KIAA0101, which provided a potential therapeutic strategy for ESCC treatment.

• KIAA0101
• circ_0005231
• esophageal squamous cell carcinoma
• miR-383-5p

Breast cancer (BC) has long been a major death threat facing women worldwide. With the development of comprehensive treatment methods, the prognosis of BC was improved but still unsatisfactory. This study was aimed to identify the key genes in BC tumorigenesis and investigate potential prognostic predictors.

Differential expression genes were analyzed in TCGA BRCA dataset using Genevestigator software. The expression profile of target gene was explored, and the correlations between selected genes with important clinical parameters were evaluated as well. The prognostic values of target genes were also carried out through Kaplan-Meier plotter OncoLnc and BC gene-expression miner.

KIAA0101 gene was selected for further analysis from the differential expression genes identified. At both mRNA and protein levels, the expression of KIAA0101 in BC was higher than that in normal tissues. Further analysis indicated that overexpression of KIAA0101 was significantly correlated with worse clinical outcome parameters. KIAA0101 was highly expressed in older patients, in the luminal group, and in patients with advanced stages. Moreover, BC patients with elevated KIAA0101 expression had worse overall survival (OS), relapse-free survival (RFS), distant metastasis-free survival (DMFS) and disease-free survival (DFS).

Taken together, KIAA0101 could be considered as a diagnostic biomarker or predictor for BC prognosis.

• KIAA0101
• breast cancer (BC)
• prognosis

Metabolic regulations play vital roles on maintaining the homeostasis of our body. Evidence have suggested that ATF3 and nuclear factor erythroid 2–related factor 2 (NRF2) are critical for maintaining cell function, metabolism, and inflammation/anti-inflammation regulations when cells are under stress, while the upstream regulators in the stressed cells remain elusive. Recent findings have shown that tricarboxylic acid cycle metabolites such as itaconate and succinate are not just mitochondrial metabolites, but rather important signaling mediators, involving in the regulations of metabolism, immune modulation. Itaconate exerts anti-inflammatory role through regulating ATF3 and NRF2 pathways under stressed conditions. In addition, itaconate inhibits succinate dehydrogenase, succinate oxidation and thus blocking succinate-mediated inflammatory processes. These findings suggest itaconate-ATF3 and itaconate-NRF2 axes are well-coordinated machineries that facilitate the rescue against cellular stress. Here, we review these fascinating discoveries, a research field may help the development of more effective therapeutic approach to manage stress-induced inflammation, tissue damage, and metabolic disorder.

Gastrointestinal (GI) cancers, including malignancies in the gastrointestinal tract and accessory organs of digestion, represent the leading cause of death worldwide due to the poor prognosis of most GI cancers. An investigation into the potential molecular targets of prediction, diagnosis, prognosis, and therapy in GI cancers is urgently required. Proliferating cell nuclear antigen (PCNA) clamp associated factor (PCLAF), which plays an essential role in cell proliferation, apoptosis, and cell cycle regulation by binding to PCNA, is a potential molecular target of GI cancers as it contributes to a series of malignant properties, including tumorigenesis, epithelial-mesenchymal transition, migration, and invasion. Furthermore, PCLAF is an underlying plasma prediction target in colorectal cancer and liver cancer. In addition to GI cancers, PCLAF is also involved in other types of cancers and autoimmune diseases. Several pivotal pathways, including the Rb/E2F pathway, NF-κB pathway, and p53-p21 cascade, are implicated in PCLAF-mediated diseases. PCLAF also contributes to some diseases through dysregulation of the p53 pathway, WNT signal pathway, MEK/ERK pathway, and PI3K/AKT/mTOR signal cascade. This review mainly describes in detail the role of PCLAF in physiological status and GI cancers. The signaling pathways involved in PCLAF are also summarized. Suppression of the interaction of PCLAF/PCNA or the expression of PCLAF might be potential biological therapeutic strategies for GI cancers.

• Proliferating cell nuclear antigen
• Proliferating cell nuclear antigen clamp associated factor
• Transcript variant
• Gastrointestinal cancers
• Signal pathway
• Biological therapeutic

PCNA-associated factor, the protein encoded by the KIAA0101/PCLAF gene, is a cell-cycle regulated oncoprotein that regulates DNA synthesis, maintenance of DNA methylation, and DNA-damage bypass, through the interaction with the human sliding clamp PCNA. KIAA0101/PCLAF is overexpressed in various cancers, including hepatocellular carcinoma (HCC). However, it remains unknown whether KIAA0101/PCLAF overexpression is coupled to gene amplification in HCC.

KIAA0101/PCLAF mRNA expression levels were assessed by quantitative real-time PCR (qRT-PCR) in 40 pairs of snap-frozen HCC and matched-non-cancerous tissues. KIAA0101/PCLAF gene copy numbers were evaluated by droplet digital PCR (ddPCR) in 36 pairs of the tissues, and protein expression was detected by immunohistochemistry (IHC) in 81 pairs of formalin-fixed paraffin-embedded (FFPE) tissues. The KIAA0101/PCLAF gene copy number alteration and RNA expression was compared by Spearman correlation. The relationships between KIAA0101 protein expression and other clinicopathological parameters, including Ki-67, p53, and HBsAg protein expression in HCC tissues, were evaluated using Chi-square test.

Our results demonstrated that KIAA0101/PCLAF mRNA levels were significantly higher in HCC than in the matched-non-cancerous tissues (p < 0.0001). The high KIAA0101/PCLAF mRNA levels in HCC were associated with poor patient survival. The KIAA0101/PCLAF gene was not amplified in HCC, and KIAA0101/PCLAF gene copy numbers were not associated with KIAA0101/PCLAF transcript levels. KIAA0101 protein was overexpressed in the majority of HCC tissues (77.8%) but was not detectable in matched-non-cancerous tissues. Significant correlations between the expression of KIAA0101 protein in HCC tissues and p53 tumor suppressor protein (p = 0.002) and Ki-67 proliferation marker protein (p = 0.017) were found. However, KIAA0101 protein levels in HCC tissues were not correlated with patient age, tumor size, serum AFP level, or the HBsAg expression.

KIAA0101/PCLAF mRNA and protein overexpression is frequently observed in HCC but without concurrent KIAA0101/PCLAF gene amplification. Significant correlations between the expression of KIAA0101 protein and p53 and Ki-67 proteins were observed in this study. Thus, detection of KIAA0101/PCLAF mRNA/protein might be used, along with the detection of p53 and Ki-67 proteins, as potential biomarkers to select candidate patients for further studies of novel HCC treatment related to these targets.

The online version contains supplementary material available at 10.1186/s12885-021-07994-3.

• Droplet digital PCR
• Ki-67 proliferation marker protein, HCC
• PCNA-associated factor (KIAA0101/PCLAF)
• p53 tumor suppressor protein
• quantitative real-time PCR

• KIAA0101
• Lung adenocarcinoma
• Lung cancer
• Proliferating cell nuclear antigen-associated factor
• Radiosensitivity

• Nasopharyngeal carcinoma
• PCLAF
• RelB
• p50

• Cellular senescence
• DNA damage
• Time-course transcriptome profiling
• Transient cell-cycle arrest

• Cell Cycle Checkpoints
• Cell Line
• Cellular Senescence
• Cholesterol/metabolism
• DNA Damage
• Humans
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Transcriptome

• ATF3
• Apoptosis
• DNA repair
• ZnO nanoparticle
• p53

• Activating Transcription Factor 3/genetics
• Activating Transcription Factor 3/metabolism
• Apoptosis/drug effects
• Bronchi/drug effects
• Bronchi/metabolism
• Bronchi/pathology
• Cells, Cultured
• DNA Damage
• DNA Repair
• Epithelial Cells/drug effects
• Epithelial Cells/metabolism
• Epithelial Cells/pathology
• Humans
• Mutagens/chemistry
• Mutagens/toxicity
• NF-E2-Related Factor 2/genetics
• NF-E2-Related Factor 2/metabolism
• Nanoparticles/chemistry
• Nanoparticles/toxicity
• Transcription, Genetic/drug effects
• Tumor Suppressor Protein p53/biosynthesis
• Tumor Suppressor Protein p53/genetics
• Zinc Oxide/chemistry
• Zinc Oxide/toxicity

• Protective effect
• RNA-seq
• Ranscriptomic analysis
• Visible red light

• KIAA0101
• bioinformatics
• cell cycle
• gastric cancer
• gene

• KIAA0101 transcript variant 2
• alternative splicing
• hepatocellular carcinoma
• isoform-selective competitor
• therapeutic drug

Paf15, which participates in DNA repair, is overexpressed in numerous solid tumors. Blocking of Paf15 inhibits the growth of many types of cancer cells; while simultaneously enhancing cellular sensitivity to UV radiation. However, its expression and function in rectal cancer (RC) remain unknown. The current study was undertaken to assess the association of Paf15 expression with RC prognosis, as well as to explore the participation of Paf15 in the response of RC cells to irradiation. Increased Paf15 expression was observed in RC tissues and associated with pTNM stage and poor survival. In vitro, Paf15 induced increased RC cell proliferation while accelerating cell cycle progression, inhibiting cell death, and protecting against gamma radiation-induced DNA damage in RC cells. In conclusion, increased Paf15 expression is associated with increased RC proliferation, decreased patient survival, and a worse radiotherapeutic response.

• Paf15
• cell cycle
• gamma radiation
• prognostic factor
• rectal cancer

Early studies indicated that TR4 nuclear receptor (TR4) may play a key role to modulate the prostate cancer progression, its potential linkage to liver cancer progression, however, remains unclear. Here we found that higher TR4 expression in hepatocellular carcinoma (HCC) cells might enhance the efficacy of cisplatin chemotherapy to better suppress the HCC progression. Knocking down TR4 with TR4-siRNA in HCC Huh7 and Hep3B cells increased cisplatin chemotherapy resistance and overexpression of TR4 with TR4-cDNA in HCC LM3 and SNU387 cells increased cisplatin chemotherapy sensitivity. Mechanism dissection found that TR4 might function through altering the ATF3 expression at the transcriptional level to enhance the cisplatin chemotherapy sensitivity, and interrupting ATF3 expression via ATF3-siRNA reversed TR4-enhanced cisplatin chemotherapy sensitivity in HCC cells. The in vivo HCC mouse model using xenografted HCC LM3 cells also confirmed in vitro cell lines data showing TR4 enhanced the cisplatin chemotherapy sensitivity. Together, these results provided a new potential therapeutic approach via altering the TR4-ATF3 signals to increase the efficacy of cisplatin to better suppress the HCC progression.

• ATF3
• TR4
• TR4 response element
• chemotherapy
• hepatocellular carcinoma

Mice lacking genes involving in the DNA damage response (DDR) are often tumor prone owing to genome instability caused by oncogenic challenges. Previous studies demonstrate that activating transcription factor 3 (ATF3), a common stress sensor, can activate the tumor suppressor p53 and regulate expression of p53 target genes upon DNA damage. However, whether ATF3 contributes to the maintenance of genome stability and tumor suppression remains unknown. Here we report that Atf3-deficient (Atf3^-/-) mice developed spontaneous tumors, and died significantly earlier than wild-type (Atf3^+/+) mice. Consistent with these results, Atf3^-/- mouse embryonic fibroblasts (MEFs) had more aberrant chromosomes and micronuclei, and were genetically unstable. Whereas we demonstrated that ATF3 activated p53 and promoted its pro-apoptotic activity in mouse thymi and small intestines, the chromosomal instability caused by Atf3 deficiency was largely dependent on the regulation of p53 by ATF3. Interestingly, loss of Atf3 also promoted spontaneous tumorigenesis in Trp53^+/- mice, but did not affect tumor formation in Trp53^-/- mice. Our results thus provide the first genetic evidence linking ATF3 to the suppression of the early development of cancer, and underscore the importance of ATF3 in the maintenance of genome integrity.

The purpose of this study was to investigate the mechanisms by which miR-183 may contribute to the phenotypic alterations associated with stress-induced senescence of human trabecular meshwork (HTM) cells.

Changes in gene expression induced by miR-183 in HTM cells were evaluated by gene array analysis, confirmed by quantitative-PCR (Q-PCR), and analyzed by MetaCore pathway analysis. Effects of miR-183 on cell proliferation were assessed by incorporation of bromodeoxyuridine incorporation, and DNA damage by CometAssay after ultraviolet (UV) irradiation in primary HTM cells, and confirmed in human diploid fibroblasts (HDF) and HeLa cells. A plasmid expressing KIAA0101 without its 3′-untranslated region (3′-UTR) was cotransfected with miR-183 to evaluate the role of KIAA0101 on the effects induced by miR-183.

miR-183 affected the expression of multiple genes involved in cell cycle regulation and DNA damage response in HTM cells. Forced expression of miR-183 in HTM and HDF resulted in a significant decrease in proliferation in primary HTM and HDF cells but not in HeLa cells. In all cell types tested, overexpression of miR-183 resulted in increased DNA damage under UV irradiation. Expression of KIAA0101 lacking the 3′-UTR region partially prevented the effects of miR-183 on cell proliferation and completely reversed the effects on UV-induced DNA damage.

Our results suggest that the observed up-regulation of miR-183 after stress-induced senescence in HTM cells may contribute to reinforce cellular senescence by inhibiting cell cycle progression through multiple gene targets and limiting the DNA repair mechanisms through inhibition of KIAA0101.

• Apoptosis
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/pathology
• Carrier Proteins/genetics
• Carrier Proteins/physiology
• Cell Line, Tumor
• Cell Proliferation
• Cyclin-Dependent Kinase 2/genetics
• Cyclin-Dependent Kinase 2/physiology
• DNA-Binding Proteins
• Esophageal Neoplasms/genetics
• Esophageal Neoplasms/pathology
• Esophageal Squamous Cell Carcinoma
• G2 Phase Cell Cycle Checkpoints
• Genes, Tumor Suppressor
• Humans
• MicroRNAs/physiology
• Prognosis
• Wnt Signaling Pathway
• beta Catenin/physiology

• CIHR

• AUTOPHAGY
• BECLIN 1
• NS5ATP9
• PROLIFERATION
• STARVATION

• ATF3
• DNA damage
• DNA repair
• UV
• apoptosis
• histone modifications
• p53
• stress response

Tat-interactive protein 60 (Tip60) is a MYST histone acetyltransferase that catalyzes acetylation of the major DNA damage kinase ATM, thereby triggering cellular signaling required for the maintenance of genomic stability upon genotoxic insults. The Tip60 activity is modulated by posttranslational modifications that alter its stability and its interactions with substrates. Here we report that activating transcription factor 3 (ATF3), a common stress mediator and a p53 activator, is a regulator of Tip60. ATF3 directly binds Tip60 at a region adjacent to the catalytic domain to promote the protein acetyltransferase activity. Moreover, the ATF3-Tip60 interaction increases the Tip60 stability by promoting USP7-mediated deubiquitination of Tip60. Consequently, knockdown of ATF3 expression leads to decreased Tip60 expression and suppression of ATM signaling as evidenced by accumulated DNA lesions and increased cell sensitivity to irradiation. Our findings thus reveal a previously unknown function of a common stress mediator in regulating Tip60 function.

• Beclin 1
• HCV
• LC3
• NS5A
• NS5ATP9
• autophagy

The main cause of death of breast cancer patients is not the primary tumor itself but the metastatic disease. Identifying breast cancer-specific signatures for metastasis and learning more about the nature of the genes involved in the metastatic process would 1) improve our understanding of the mechanisms of cancer progression and 2) reveal new therapeutic targets. Previous studies showed that the transcriptional regulator megakaryoblastic leukemia-1 (Mkl1) induces tenascin-C expression in normal and transformed mammary epithelial cells. Tenascin-C is known to be expressed in metastatic niches, is highly induced in cancer stroma and promotes breast cancer metastasis to the lung.

Using HC11 mammary epithelial cells overexpressing different Mkl1 constructs, we devised a subtractive transcript profiling screen to identify the mechanism by which Mkl1 induces a gene set co-regulated with tenascin-C. We performed computational analysis of the Mkl1 target genes and used cell biological experiments to confirm the effect of these gene products on cell behavior. To analyze whether this gene set is prognostic of accelerated cancer progression in human patients, we used the bioinformatics tool GOBO that allowed us to investigate a large breast tumor data set linked to patient data.

We discovered a breast cancer-specific set of genes including tenascin-C, which is regulated by Mkl1 in a SAP domain-dependent, serum response factor-independent manner and is strongly implicated in cell proliferation, cell motility and cancer. Downregulation of this set of transcripts by overexpression of Mkl1 lacking the SAP domain inhibited cell growth and cell migration. Many of these genes are direct Mkl1 targets since their promoter-reporter constructs were induced by Mkl1 in a SAP domain-dependent manner. Transcripts, most strongly reduced in the absence of the SAP domain were mechanoresponsive. Finally, expression of this gene set is associated with high-proliferative poor-outcome classes in human breast cancer and a strongly reduced survival rate for patients independent of tumor grade.

This study highlights a crucial role for the transcriptional regulator Mkl1 and its SAP domain during breast cancer progression. We identified a novel gene set that correlates with bad prognosis and thus may help in deciding the rigor of therapy.

• Base Sequence
• Binding Sites
• Carrier Proteins/genetics
• Carrier Proteins/metabolism
• Cell Cycle/physiology
• Cell Line
• Chromatin/metabolism
• DNA Replication
• DNA-Binding Proteins
• E2F Transcription Factors/metabolism
• Gene Expression
• Gene Knockdown Techniques
• Humans
• Nucleotide Motifs
• Promoter Regions, Genetic
• Protein Binding
• Retinoblastoma Protein/genetics
• Retinoblastoma Protein/metabolism
• S Phase/genetics
• Signal Transduction

Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR–deficient Csa^−/− and Csb^−/− CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER–deficient Xpa^−/− and Xpc^−/− XP mice, but also occurred in Xpd^XPCS mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR–deficient mice are compatible with focal dysmyelination in CS patients. Both TCR–deficient and NER–deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa^−/−, Csb^−/−) or highly sporadic (Xpa^−/−, Xpc^−/−) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR–deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa^−/− and Csb^−/− TCR–deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities in CS, neuron-specific inactivation of NER in TCR–deficient mice represents a valuable model for the role of NER in neuronal maintenance and survival.

Metabolism produces reactive oxygen species that damage our DNA and other cellular components, and as such it contributes to the aging process, including neuronal degeneration. Accordingly, genetic disorders associated with impaired DNA damage repair are frequently associated with premature onset of aging pathology in a variety of tissues, including the brain. This is well-illustrated by the progeroid DNA repair syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS), in which patients suffer from defects in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively. We have used a panel of XP and CS mice (including conditional double-mutant animals) to systematically investigate the impact of NER and TCR defects on neuronal degeneration. We have shown that, whereas a TCR defect causes white matter pathology, a NER defect can result in age related cumulative loss of neurons. These findings well match the neuropathology observed in CS and XP patients, underscoring the impact of spontaneous DNA damage in the onset of neuronal aging. Therefore, the XP and CS mouse models serve as valuable tools to delineate intervention strategies that combat age-associated pathology of the brain.

KIAA0101 is a proliferating cell nuclear antigen-associated factor that is overexpressed in some human malignancies. Adrenocortical neoplasm is one of the most common human neoplasms for which the molecular causes are poorly understood. Moreover, it is difficult to distinguish between localized benign and malignant adrenocortical tumors. For these reasons, we studied the expression, function and possible mechanism of dysregulation of KIAA0101 in human adrenocortical neoplasm.

KIAA0101 mRNA and protein expression levels were determined in 112 adrenocortical tissue samples (21 normal adrenal cortex, 80 benign adrenocortical tumors, and 11 adrenocortical carcinoma (ACC). SiRNA knockdown was used to determine the functional role of KIAA0101 on cell proliferation, cell cycle, apoptosis, soft agar anchorage independent growth and invasion in the ACC cell line, NCI-H295R. In addition, we explored the mechanism of KIAA0101 dysregulation by examining the mutational status. KIAA0101 mRNA (9.7 fold) and protein expression were significantly higher in ACC (p<0.0001). KIAA0101 had sparse protein expression in only a few normal adrenal cortex samples, which was confined to adrenocortical progenitor cells. KIAA0101 expression levels were 84% accurate for distinguishing between ACC and normal and benign adrenocortical tumor samples. Knockdown of KIAA0101 gene expression significantly decreased anchorage independent growth by 80% and invasion by 60% (p = 0.001; p = 0.006). We found no mutations in KIAA0101 in ACC.

KIAA0101 is overexpressed in ACC. Our data supports that KIAA0101 is a marker of cellular proliferation, promotes growth and invasion, and is a good diagnostic marker for distinguishing benign from malignant adrenocortical neoplasm.

The Paf oncogene is highly expressed in cycling hematopoietic stem cells (HSCs) and is required for the development of long-term HSCs.

Hematopoietic stem cells (HSCs) self-renew to maintain the lifelong production of all blood populations. Here, we show that the proliferating cell nuclear antigen–associated factor (Paf) is highly expressed in cycling bone marrow HSCs and plays a critical role in hematopoiesis. Mice lacking Paf exhibited reduced bone marrow cellularity; reduced numbers of HSCs and committed progenitors; and leukopenia. These phenotypes are caused by a cell-intrinsic blockage in the development of long-term (LT)-HSCs into multipotent progenitors and preferential loss of lymphoid progenitors caused by markedly increased p53-mediated apoptosis. In addition, LT-HSCs from Paf^−/− mice had increased levels of reactive oxygen species (ROS), failed to maintain quiescence, and were unable to support LT hematopoiesis. The loss of lymphoid progenitors was likely due the increased levels of ROS in LT-HSCs caused by treatment of Paf^−/− mice with the anti-oxidant N-acetylcysteine restored lymphoid progenitor numbers to that of Paf^+/+ mice. Collectively, our studies identify Paf as a novel and essential regulator of early hematopoiesis.

We collected a massive and heterogeneous dataset of 20 255 gene expression profiles (GEPs) from a variety of human samples and experimental conditions, as well as 8895 GEPs from mouse samples. We developed a mutual information (MI) reverse-engineering approach to quantify the extent to which the mRNA levels of two genes are related to each other across the dataset. The resulting networks consist of 4 817 629 connections among 20 255 transcripts in human and 14 461 095 connections among 45 101 transcripts in mouse, with a inter-species conservation of 12%. The inferred connections were compared against known interactions to assess their biological significance. We experimentally validated a subset of not previously described protein–protein interactions. We discovered co-expressed modules within the networks, consisting of genes strongly connected to each other, which carry out specific biological functions, and tend to be in physical proximity at the chromatin level in the nucleus. We show that the network can be used to predict the biological function and subcellular localization of a protein, and to elucidate the function of a disease gene. We experimentally verified that granulin precursor (GRN) gene, whose mutations cause frontotemporal lobar degeneration, is involved in lysosome function. We have developed an online tool to explore the human and mouse gene networks.

• beta cell
• cell cycle
• fignl1
• g7e
• islets of langerhans
• pregnancy
• replication

• Animals
• Cell Proliferation
• Cells, Cultured
• Female
• Gene Expression Profiling
• Gene Knockdown Techniques
• Genes, cdc
• HLA Antigens/genetics
• HLA Antigens/metabolism
• Insulin-Secreting Cells/metabolism
• Islets of Langerhans/metabolism
• Male
• Mice
• Mice, Inbred C57BL
• Pregnancy
• RNA, Messenger/analysis
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Time Factors

To identify new genetic regulators of cellular aging and senescence, we performed genome-wide comparative RNA profiling with selected human cellular model systems, reflecting replicative senescence, stress-induced premature senescence, and distinct other forms of cellular aging. Gene expression profiles were measured, analyzed, and entered into a newly generated database referred to as the GiSAO database. Bioinformatic analysis revealed a set of new candidate genes, conserved across the majority of the cellular aging models, which were so far not associated with cellular aging, and highlighted several new pathways that potentially play a role in cellular aging. Several candidate genes obtained through this analysis have been confirmed by functional experiments, thereby validating the experimental approach. The effect of genetic deletion on chronological lifespan in yeast was assessed for 93 genes where (i) functional homologues were found in the yeast genome and (ii) the deletion strain was viable. We identified several genes whose deletion led to significant changes of chronological lifespan in yeast, featuring both lifespan shortening and lifespan extension. In conclusion, an unbiased screen across species uncovered several so far unrecognized molecular pathways for cellular aging that are conserved in evolution.

• Adult
• Cellular Senescence/genetics
• Child, Preschool
• Databases, Genetic
• Evolution, Molecular
• Gene Expression Regulation
• Humans
• Middle Aged
• Oxidative Stress
• Saccharomyces cerevisiae/genetics

• M 903 Austrian Science Fund FWF
• S 9302 Austrian Science Fund FWF