• Binding partners
• Cellular processes
• RSK2
• Signal transduction
• Signaling nodes

• Humans
• Ribosomal Protein S6 Kinases, 90-kDa/metabolism
• Ribosomal Protein S6 Kinases, 90-kDa/antagonists & inhibitors
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/pathology
• Signal Transduction/drug effects
• Signal Transduction/physiology
• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Cell Proliferation/drug effects

• M-2021-B0008004 Catholic University of Korea
• RS-2023-NR076969 Ministry of Science, ICT and Future Planning

• RSK2
• anti-cancer
• apoptosis
• inhibitor.
• metastasis
• natural products
• proliferation

• Humans
• Ribosomal Protein S6 Kinases, 90-kDa/antagonists & inhibitors
• Ribosomal Protein S6 Kinases, 90-kDa/metabolism
• Neoplasms/drug therapy
• Neoplasms/pathology
• Neoplasms/metabolism
• Biological Products/pharmacology
• Biological Products/chemistry
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Cell Proliferation/drug effects
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/chemistry
• Animals
• Apoptosis/drug effects

• 81502958 National Natural Science Foundation of China
• BK20150286 National Science Foundation of Jiangsu Province
• SS202086, SKJY2021032, 2022SS29 Minsheng Science and Technology Project of Suzhou
• SZWZYTD202204 Technology Innovation Team of Synthesis and Research of Small Molecule Targeted Anticancer Drugs
• KYCX22_3295 Postgraduate Research & Practice Innovation Program of Jiangsu Province

• chromatin remodelling
• kinases

• M-2024-B0002-00041 Catholic University of Korea (The Catholic University of Korea)
• 2023R1A2C2003059 Ministry of Science, ICT and Future Planning (MSIP)

• Mirk/Dyrk1B kinase
• X-ray crystal structures
• apoptosis
• cancer
• cancer stem cells
• inhibitors
• quiescence
• targeted cancer therapy

• ΤΑΑ TAEDR-0535850 Funded by the General Secretariat for Research and Innovation under the action "National research network to elucidate the genetic basis of Alzheimer's and Parkinson's neurodegenerative diseases, detect reliable biomarkers, and develop innovative computat

• Adenosine monophosphate-activated protein kinase
• Bladder cancer
• Epithelial bladder cells
• Metformin
• Nitrate

• Biomechanics
• Epigenetics
• Nucleus
• Target therapy
• Tumor

• Humans
• Epigenesis, Genetic
• Neoplasms/genetics
• Neoplasms/pathology
• Carcinogenesis/genetics
• Cell Movement
• Tumor Microenvironment

• National Natural Science Foundation of China
• Natural Science Foundation of Chongqing
• Natural Science Foundation of Hubei

• 5-fluorouracil (5-FU)
• RSK2
• base editors
• functional phosphoproteomics
• screen

• Humans
• Drug Resistance, Neoplasm/genetics
• Clustered Regularly Interspaced Short Palindromic Repeats
• Fluorouracil/pharmacology
• Fluorouracil/therapeutic use
• Protein Kinases/genetics
• Protein Kinases/metabolism
• Protein Kinases/pharmacology
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Adenine/pharmacology
• Adenine/therapeutic use
• Amino Acids/genetics
• Amino Acids/pharmacology
• Amino Acids/therapeutic use
• Cytosine/pharmacology
• Cytosine/therapeutic use
• p21-Activated Kinases/genetics
• p21-Activated Kinases/metabolism
• p21-Activated Kinases/pharmacology

• 2020B1515020018 Excellent Youth Foundation of Guangdong Scientific Committee
• 2021YFA0804702 National Key Research and Development Program
• 2018YFC1004700 National Key Research and Development Program
• 17JC1420103 Local Grants
• National Key Research and Development Program

Histone H2AX (H2A.X) is a variant of the histone H2A family. Phosphorylation of H2A.X is a marker of DNA strand breaks and the presence or absence of H2A.X is closely related to tumor susceptibility and drug resistance. The present study found that the activity of the serine/threonine kinase Akt was negatively associated with H2A.X phosphorylated at the Ser16 site (H2A.X S16ph), but the mechanism of the inverse relationship remains elusive. The aim of the present study was to elucidate the mechanism of action between Akt and H2A.X S16ph and the exact role of this mechanism. Western blot analysis was performed to detect the regulatory association between p-Akt and H2A.X S16ph/p-RSK2, and immunoprecipitation and chromatin immunoprecipitation were performed to prove that Akt, RSK2 and H2A.X combine and interact in human breast cancer cells. The changes of cellular proliferation and migration induced by the interaction of Akt, RSK2 and H2A.X was determined by MTT, soft agar colony formation and cell migration experiments. The effect of interaction of Akt, RSK2 and H2A.X on cancer-promoting genes, such as PSAT-1 was determined via reverse transcription-quantitative PCR analysis. The current study indicated that the serine/threonine kinase ribosomal S6 kinase 2 (RSK2) as a kinase of H2A.X could be phosphorylated by Akt at Ser19 site. Moreover, Akt positively regulated the phosphorylation of RSK2 to inhibit phosphorylation of H2A.X, thereby affecting the affinity between RSK2 and substrate histone, promoting the survival and migration of breast cancer cells. In conclusion, Akt-mediated phosphorylation of RSK2 regulated the phosphorylation of H2A.X, thereby promoting oncogenic activity. This finding provides new insights to understand the pathogenesis and treatment mechanisms of breast cancer.

• Akt
• breast cancer
• histone H2AX
• phosphorylation
• serine/threonine kinase ribosomal S6 kinase 2

• Cancer
• Cancer stem cells
• Cell proliferation/differentiation
• Cell survival
• Dual-specificity tyrosine-regulated kinase 1B
• Hedgehog
• Minibrain-related kinase
• Quiescence
• Stem cells

The p38 mitogen-activated protein kinase (p38MAPK, termed here p38) cascade is a central signaling pathway that transmits stress and other signals to various intracellular targets in the cytoplasm and nucleus. More than 150 substrates of p38α/β have been identified, and this number is likely to increase. The phosphorylation of these substrates initiates or regulates a large number of cellular processes including transcription, translation, RNA processing and cell cycle progression, as well as degradation and the nuclear translocation of various proteins. Being such a central signaling cascade, its dysregulation is associated with many pathologies, particularly inflammation and cancer. One of the hallmarks of p38α/β signaling is its stimulated nuclear translocation, which occurs shortly after extracellular stimulation. Although p38α/β do not contain nuclear localization or nuclear export signals, they rapidly and robustly translocate to the nucleus, and they are exported back to the cytoplasm within minutes to hours. Here, we describe the physiological and pathological roles of p38α/β phosphorylation, concentrating mainly on the ill-reviewed regulation of p38α/β substrate degradation and nuclear translocation. In addition, we provide information on the p38α/β ’s substrates, concentrating mainly on the nuclear targets and their role in p38α/β functions. Finally, we also provide information on the mechanisms of nuclear p38α/β translocation and its use as a therapeutic target for p38α/β-dependent diseases.

• cancer
• inflammation
• nuclear translocation
• p38MAPK
• β-like importins

• Arsenic/toxicity
• Carcinogens/toxicity
• DNA Repair/drug effects
• Humans
• Reactive Nitrogen Species/metabolism
• Reactive Oxygen Species/metabolism

• R01 ES029749 NIEHS NIH HHS
• T32 ES018827 NIEHS NIH HHS

TRAF6, a well-known adapter molecule, plays pivotal role in TLR/IL-1R associated signaling pathway. Although TRAF6 has been shown to have oncogenic activity in various malignant tumors, the details remain unclear. In this study, we demonstrated that TRAF6 facilitates Ras (G12V) and EGF-induced cellular transformation through EGFR. Silencing of TRAF6 expression significantly downregulated AP-1 activity, as well as MMP-2,9 expression after EGF stimulation. Furthermore, we found that TRAF6 plays an essential role in cutaneous squamous cell carcinoma (cSCC) malignant phenotypes, affecting cell growth and migration. CD147/Basigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is over-expressed in tumors and induces tumorigenesis. Our results showed that CD147 formed complex with EGFR and TRAF6. Knockdown of TRAF6 disrupted the CD147-EGFR complex, thereby inducing EGFR endocytosis. Therefore, TRAF6 might be a novel molecular target for cSCC prevention or therapy.

Renal Cell Carcinoma (RCC) in humans is positively influenced by oxidative stress status in kidneys. We recently reported that adaptive response to low level of chronic oxidative stress induces malignant transformation of immortalized human renal tubular epithelial cells. Epigenetic alterations in human RCC are well documented, but its role in oxidative stress-induced malignant transformation of kidney cells is not known. Therefore, the objective of this study was to evaluate the potential role of epigenetic changes in chronic oxidative stress-induced malignant transformation of HK-2, human renal tubular epithelial cells. The results revealed aberrant expression of epigenetic regulatory genes involved in DNA methylation (DNMT1, DNMT3a and MBD4) and histone modifications (HDAC1, HMT1 and HAT1) in HK-2 cells malignantly transformed by chronic oxidative stress. Additionally, both in vitro soft agar assay and in vivo nude mice study showing decreased tumorigenic potential of malignantly transformed HK-2 cells following treatment with DNA de-methylating agent 5-aza 2’ dC further confirmed the crucial role of DNA hypermethyaltion in oxidative stress-induced malignant transformation. Changes observed in global histone H3 acetylation (H3K9, H3K18, H3K27 and H3K14) and decrease in phospho-H2AX (Ser139) also suggest potential role of histone modifications in increased survival and malignant transformation of HK-2 cells by oxidative stress. In summary, the results of this study suggest that epigenetic reprogramming induced by low levels of oxidative stress act as driver for malignant transformation of kidney epithelial cells. Findings of this study are highly relevant in potential clinical application of epigenetic-based therapeutics for treatments of kidney cancers.

• DNA methylation
• epigenetics
• histone modification
• kidney cancer
• oxidative stress

• Kinase
• Metastasis
• PRPK
• Phosphorylation
• TOPK

• Chk1
• Cyclin B1
• Premature mitosis
• S/M checkpoint
• γH2AX

The therapeutic strategies against acute myeloid leukemia (AML) have hardly been modified over four decades. Although resulting in a favorable outcome in young patients, older individuals, the most affected population, do not respond adequately to therapy. Intriguingly, the mechanisms responsible for AML cells chemoresistance/susceptibility are still elusive. Mounting evidence has shed light on the relevance of proteolytic systems (autophagy and ubiquitin-proteasome system, UPS), as well as the AMPK pathway, in AML biology and treatment, but their exact role is still controversial. Herein, two AML cell lines (HL-60 and KG-1) were exposed to conventional chemotherapeutic agents (cytarabine and/or doxorubicin) to assess the relevance of autophagy and UPS on AML cells’ response to antileukemia drugs. Our results clearly showed that the antileukemia agents target both proteolytic systems and the AMPK pathway. Doxorubicin enhanced UPS activity while drugs’ combination blocked autophagy specifically on HL-60 cells. In contrast, KG-1 cells responded in a more subtle manner to the drugs tested consistent with the higher UPS activity of these cells. In addition, the data demonstrates that autophagy may play a protective role depending on AML subtype. Specific modulators of autophagy and UPS are, therefore, promising targets for combining with standard therapeutic interventions in some AML subtypes.

• AMPK pathway
• acute myeloid leukemia (AML)
• chemotherapeutic agents
• macroautophagy
• ubiquitin-proteasome system (UPS)

• Animals
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Caspase 3/metabolism
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Cyclin-Dependent Kinase Inhibitor p21/metabolism
• Esophageal Neoplasms/drug therapy
• Esophageal Neoplasms/pathology
• G2 Phase Cell Cycle Checkpoints/drug effects
• Humans
• Indoles/pharmacology
• Male
• Mice, SCID
• Middle Aged
• Nitrobenzenes/pharmacology
• Reactive Oxygen Species/metabolism
• Signal Transduction
• Transcription Factor AP-1/metabolism
• Tumor Burden/drug effects
• Xenograft Model Antitumor Assays

• R37CA081064 NCI NIH HHS
• R21 CA172457 NCI NIH HHS
• CA172457 NCI NIH HHS
• R37 CA081064 NCI NIH HHS
• R01 CA166011 NCI NIH HHS
• CA166011 NCI NIH HHS

• DNA methylation
• chromatin conformation
• epigenetics
• histone modification
• non-coding RNA

Ribosomal S6 Kinase 2 (RSK2) is a member of the p90^RSK family of serine/threonine kinases, which are widely expressed and respond to many growth factors, peptide hormones, and neurotransmitters. Loss-of function mutations in the RPS6KA3 gene, which encodes the RSK2 protein, have been implicated in Coffin-Lowry Syndrome (CLS), an X-linked mental retardation disorder associated with cognitive deficits and behavioral impairments. However, the cellular and molecular mechanisms underlying this neurological disorder are not known. Recent evidence suggests that defective DNA damage signaling might be associated with neurological disorders, but the role of RSK2 in the DNA damage pathway remains to be elucidated. Here, we show that Adriamycin-induced DNA damage leads to the phosphorylation of RSK2 at Ser227 and Thr577 in the chromatin fraction, promotes RSK2 nuclear translocation, and enhances RSK2 and Atm interactions in the nuclear fraction. Furthermore, using RSK2 knockout mouse fibroblasts and RSK2-deficient cells from CLS patients, we demonstrate that ablation of RSK2 impairs the phosphorylation of Atm at Ser1981 and the phosphorylation of p53 at Ser18 (mouse) or Ser15 (human) in response to genotoxic stress. We also show that RSK2 affects p53-mediated downstream cellular events in response to DNA damage, that RSK2 knockout relieves cell cycle arrest at the G2/M phase, and that an increased number of γH2AX foci, which are associated with defects in DNA repair, are present in RSK2-deficient cells. Taken together, our findings demonstrated that RSK2 plays an important role in the DNA damage pathway that maintains genomic stability by mediating cell cycle progression and DNA repair.

• Ataxia Telangiectasia Mutated Proteins/metabolism
• DNA Damage
• Genomic Instability
• Humans
• Mutagens/toxicity
• Phosphorylation
• Ribosomal Protein S6 Kinases, 90-kDa/metabolism
• Tumor Suppressor Protein p53/metabolism

• RSK2
• RSK2 inhibitors
• carcinogenesis
• chemoprevention
• skin cancer

• Autoantigens/genetics
• Autoantigens/metabolism
• Centromere Protein A
• Chromatin/physiology
• Chromosomal Proteins, Non-Histone/genetics
• Chromosomal Proteins, Non-Histone/metabolism
• Gene Components
• Genetic Variation
• Histone Chaperones/genetics
• Histone Chaperones/metabolism
• Histones/chemistry
• Histones/genetics
• Histones/metabolism
• Humans
• Models, Molecular
• Neoplasms/genetics
• Neoplasms/physiopathology

• R01 CA154683 NCI NIH HHS
• T32 CA078207 NCI NIH HHS
• T32-CA078207 NCI NIH HHS
• R01CA154683 NCI NIH HHS