TTLL12 has a potential oncogenic activity, suppression of ligation of nitrotyrosine to the C-terminus of detyrosinated α-tubulin, that can be overcome by molecules identified by screening a compound library.

Tubulin tyrosine ligase 12 (TTLL12) is a promising target for therapeutic intervention since it has been implicated in tumour progression, the innate immune response to viral infection, ciliogenesis and abnormal cell division. It is the most mysterious of a fourteen-member TTL/TTLL family, since, although it is the topmost conserved in evolution, it does not have predicted enzymatic activities. TTLL12 seems to act as a pseudo-enzyme that modulates various processes indirectly.

The Multifaceted Role of Human Dickkopf-3 (DKK-3) in Development, Immune Modulation and Cancer.

The human Dickkopf (DKK) family includes four main secreted proteins, DKK-1, DKK-2, DKK-3, and DKK-4, as well as the DKK-3 related protein soggy (Sgy-1 or DKKL1). These glycoproteins play crucial roles in various biological processes, and especially modulation of the Wnt signaling pathway. DKK-3 is distinct, with its multifaceted roles in development, stem cell differentiation and tissue homeostasis.

A novel ΔNp63-dependent immune mechanism improves prognosis of HPV-related head and neck cancer.

Background: Deconvoluting the heterogenous prognosis of Human Papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OSCC) is crucial for enhancing patient care, given its rapidly increasing incidence in western countries and the adverse side effects of OSCC treatments.

Methods: Transcriptomic data from HPV-positive OSCC samples were analyzed using unsupervised hierarchical clustering, and clinical relevance was evaluated using Kaplan-Meier analysis. HPV-positive OSCC cell line models were used in functional analyses and phenotypic assays to assess cell migration and invasion, response to cisplatin, and phagocytosis by macrophages .

Preferential Response of Basal-Like Head and Neck Squamous Cell Carcinoma Cell Lines to EGFR-Targeted Therapy Depending on -Driven Oncogenic Addiction.

The management of locally advanced head and neck squamous cell carcinoma (HNSCC) with Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), achieves only moderate response rates, and clinical trials that evaluated EGFR-blockade with tyrosine kinase inhibitors (TKI) yielded disappointing results. Inter-tumor heterogeneity may hinder the therapeutic efficiency of anti-EGFR treatments. HNSCC heterogeneity was addressed in several studies, which all converged towards the definition of molecular subgroups.

An easy method for preparation of Cre-loxP regulated fluorescent adenoviral expression vectors and its application for direct reprogramming into hepatocytes.

The recombinant adenoviral gene expression system is a powerful tool for gene delivery. However, it is difficult to obtain high titers of infectious virus, principally due to the toxicity of the expressed gene which affects on virus replication in the host HEK293 cells. To avoid these problems, we generated a Cre-loxP-regulated fluorescent universal vector (termed pAxCALRL).

XRP44X, an Inhibitor of Ras/Erk Activation of the Transcription Factor Elk3, Inhibits Tumour Growth and Metastasis in Mice.

Transcription factors have an important role in cancer but are difficult targets for the development of tumour therapies. These factors include the Ets family, and in this study Elk3 that is activated by Ras oncogene /Erk signalling, and is involved in angiogenesis, malignant progression and epithelial-mesenchymal type processes. We previously described the identification and in-vitro characterisation of an inhibitor of Ras / Erk activation of Elk3 that also affects microtubules, XRP44X.

Endothelial depletion of murine SRF/MRTF provokes intracerebral hemorrhagic stroke.

Intracerebral hemorrhagic stroke and vascular dementia are age- and hypertension-associated manifestations of human cerebral small vessel disease (SVD). Cerebral microvessels are formed by endothelial cells (ECs), which are connected through tight junctions, adherens junctions, and stabilizing basement membrane structures. These endothelial connections ensure both vessel stability and blood-brain barrier (BBB) functions, the latter enabling selective exchange of ions, bioactive molecules, and cells between the bloodstream and brain tissue.

Human Papillomavirus-related tumours of the oropharynx display a lower tumour hypoxia signature.

Objectives: Human Papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OSCC) patients have improved prognosis compared to other head and neck (HNSCC) cancers. Since poor prognosis is associated with tumour hypoxia, we studied whether the hypoxic response is different in HPV-related cells and tumours.

Material And Methods: HPV-positive and -negative cells were incubated in hypoxia and analyzed by qRTPCR, western blotting and cell proliferation assays.

The oncogenic MicroRNA Hsa-miR-155-5p targets the transcription factor ELK3 and links it to the hypoxia response.

The molecular response to hypoxia is a critical cellular process implicated in cancer, and a target for drug development. The activity of the major player, HIF1α, is regulated at different levels by various factors, including the transcription factor ELK3. The molecular mechanisms of this intimate connection remain largely unknown.

Elk3 deficiency causes transient impairment in post-natal retinal vascular development and formation of tortuous arteries in adult murine retinae.

Serum Response Factor (SRF) fulfills essential roles in post-natal retinal angiogenesis and adult neovascularization. These functions have been attributed to the recruitment by SRF of the cofactors Myocardin-Related Transcription Factors MRTF-A and -B, but not the Ternary Complex Factors (TCFs) Elk1 and Elk4. The role of the third TCF, Elk3, remained unknown.

Crosstalk between Mdm2, p53 and HIF1-α: distinct responses to oxygen stress and implications for tumour hypoxia.

The E3 ubiquitin ligase Mdm2 regulates two transcription factors, p53 and HIF1α, which appear to be tailored towards different and specific roles within the cell, the DNA damage and hypoxia responses, respectively. However, evidence increasingly points towards the interplay between these factors being crucial for the regulation of cellular metabolism and survival in times of oxygen stress, which has particular relevance for tumour formation. Mdm2, p53 and HIF1α all respond to hypoxia, and intriguingly, have distinct roles depending on the level of hypoxia.

A poor prognosis subtype of HNSCC is consistently observed across methylome, transcriptome, and miRNome analysis.

Purpose: Distant metastasis after treatment is observed in about 20% of squamous cell carcinoma of the head and neck (HNSCC). In the absence of any validated robust biomarker, patients at higher risk for metastasis cannot be provided with tailored therapy. To identify prognostic HNSCC molecular subgroups and potential biomarkers, we have conducted genome-wide integrated analysis of four omic sets of data.

Tubulin tyrosine ligase like 12, a TTLL family member with SET- and TTL-like domains and roles in histone and tubulin modifications and mitosis.

hTTLL12 is a member of the tubulin tyrosine ligase (TTL) family that is highly conserved in phylogeny. It has both SET-like and TTL-like domains, suggesting that it could have histone methylation and tubulin tyrosine ligase activities. Altered expression of hTTLL12 in human cells leads to specific changes in H4K20 trimethylation, and tubulin detyrosination, hTTLL12 does not catalyse histone methylation or tubulin tyrosination in vitro, as might be expected from the lack of critical amino acids in its SET-like and TTLL-like domains.

The NEDD8 conjugation pathway regulates p53 transcriptional activity and head and neck cancer cell sensitivity to ionizing radiation.

Human papillomavirus (HPV)-related oropharyngeal cancer represents a distinct head and neck squamous cell carcinoma (HNSCC) subpopulation, with improved disease-free and overall survival. In general, HPV-positive HNSCCs express wild-type TP53, which could explain its increased radiosensitivity. However, the molecular mechanisms underlying this higher sensitivity remain elusive.

CD8-alpha T-cell infiltration in human papillomavirus-related oropharyngeal carcinoma correlates with improved patient prognosis.

Patients with human papillomavirus (HPV)-related oropharyngeal tumors display improved prognosis. The biological basis of this tumor phenotype is poorly understood. We investigated whether increased lymphocyte infiltrate in HPV-positive oropharyngeal squamous cell carcinomas could account for better prognosis.

c-Jun N-terminal kinase mediates microtubule-depolymerizing agent-induced microtubule depolymerization and G2/M arrest in MCF-7 breast cancer cells.

Microtubule-binding agents (MBAs) form one of the most important anticancer-drug families, but their molecular mechanisms are poorly understood. MBAs such as paclitaxel (PTX) stabilize microtubules, whereas XRP44X (a novel pyrazole) and combretastatins A4 (CA4) destabilize microtubules. These two different types of MBAs have potent antitumor activity.

A review of post-translational modifications and subcellular localization of Ets transcription factors: possible connection with cancer and involvement in the hypoxic response.

Post-translational modifications and subcellular localizations modulate transcription factors, generating a code that is deciphered into an activity. We describe our current understanding of these processes for Ets factors, which have recently been recognized for their importance in various biological processes. We present the global picture for the family, and then focus on particular aspects related to cancer and hypoxia.

ANO1 amplification and expression in HNSCC with a high propensity for future distant metastasis and its functions in HNSCC cell lines.

Background: Head and neck squamous cell carcinoma (HNSCC) is associated with poor survival. To identify prognostic and diagnostic markers and therapeutic targets, we studied ANO1, a recently identified calcium-activated chloride channel (CaCC).

Methods: High-resolution genomic and transcriptomic microarray analysis and functional studies using HNSCC cell line and CaCC inhibitors.

Ternary complex factors SAP-1 and Elk-1, but not net, are functionally equivalent in thymocyte development.

The ternary complex factors (TCFs; SAP-1, Elk-1, and Net) are serum response factor cofactors that share many functional properties and are coexpressed in many tissues. SAP-1, the predominant thymus TCF, is required for thymocyte positive selection. In this study, we assessed whether the different TCFs are functionally equivalent.

Epigenetic regulation of p16Ink4a and Arf by JDP2 in cellular senescence.

In response to accumulating cellular stress, cells protect themselves from abnormal growth by entering the senescent stage. Senescence is controlled mainly by gene products from the p16Ink4a/Arf locus. In mouse cells, the expression of p16Ink4a and Arf increases continuously during proliferation in cell culture.

Involvement of net and Hif1alpha in distinct yet intricately linked hypoxia-induced signaling pathways.

The present study compares negative Ets transcription factor (Net) and hypoxia-inducible factor 1alpha (HIF1alpha) regulation by hypoxia. Their protein stabilities are differently regulated by hypoxia, defining three periods in the kinetics: normoxia (high Net levels and low HIF1alpha levels), early hypoxia (high levels of Net and HIF1alpha), and late hypoxia (degradation of Net and HIF1alpha). Modulators of prolyl hydroxylase domain protein (PHD) activity induce a mobility shift of Net, similar to HIF1alpha, suggesting that post-translational modifications of both factors depend on PHD activity.

Regulation of MCP-1 chemokine transcription by p53.

Background: Our previous studies showed that the expression of the monocyte-chemoattractant protein (MCP)-1, a chemokine, which triggers the infiltration and activation of cells of the monocyte-macrophage lineage, is abrogated in human papillomavirus (HPV)-positive premalignant and malignant cells. In silico analysis of the MCP-1 upstream region proposed a putative p53 binding side about 2.5 kb upstream of the transcriptional start.

The expression of ELK transcription factors in adult DRG: Novel isoforms, antisense transcripts and upregulation by nerve damage.

ELK transcription factors are known to be expressed in a number of regions in the nervous system. We show by RT-PCR that the previously described Elk1, Elk3/Elk3b/Elk3c and Elk4 mRNAs are expressed in adult dorsal root ganglia (DRG), together with the novel alternatively spliced isoforms Elk1b, Elk3d and Elk4c/Elk4d/Elk4e. These isoforms are also expressed in brain, heart, kidney and testis.

Tubulin tyrosine ligase like 12 links to prostate cancer through tubulin posttranslational modification and chromosome ploidy.

Prostate cancer is a common cause of death, and an important goal is to establish the pathways and functions of causative genes. We isolated RNAs that are differentially expressed in macrodissected prostate cancer samples. This study focused on 1 identified gene, TTLL12, which was predicted to modify tubulins, an established target for tumor therapy.