The Biochemical Literacy Framework: Inviting pedagogical innovation in higher education.

When developing meaningful curricula, institutions must engage with the desired disciplinary attributes of their graduates. Successfully employed in several areas, including psychology and chemistry, disciplinary literacies provide structure for the development of core competencies-pursuing progressive education. To this end, we have sought to develop a comprehensive blueprint of a graduate biochemist, providing detailed insight into the development of skills in the context of disciplinary knowledge. The Biochemical Literacy Framework (BCLF) aspires to encourage innovative course design in both the biochemical field and beyond through stimulating discussion among individuals developing undergraduate biochemistry degree courses based on pedagogical best practice. Here, we examine the concept of biochemical literacy aiming to start answering the question: What must individuals do and know to approach and transform ideas in the context of the biochemical sciences? The BCLF began with the guidance published by relevant learned societies - including the Royal Society of Biology, the Biochemical Society, the American Society for Biochemistry and Molecular Biology and the Quality Assurance Agency, before considering relevant pedagogical literature. We propose that biochemical literacy is comprised of seven key skills: critical thinking, self-management, communication, information literacy, visual literacy, practical skills and content knowledge. Together, these form a dynamic, highly interconnected and interrelated meta-literacy supporting the use of evidence-based, robust learning techniques. The BCLF is intended to form the foundation for discussion between colleagues, in addition to forming the groundwork for both pragmatic and exploratory future studies into facilitating and further defining biochemical literacy.

Protein recognition by short peptide reversible inhibitors of the chromatin-modifying LSD1/CoREST lysine demethylase.

The combinatorial assembly of protein complexes is at the heart of chromatin biology. Lysine demethylase LSD1(KDM1A)/CoREST beautifully exemplifies this concept. The active site of the enzyme tightly associates to the N-terminal domain of transcription factors of the SNAIL1 family, which therefore can competitively inhibit the binding of the N-terminal tail of the histone substrate. Our enzymatic, crystallographic, spectroscopic, and computational studies reveal that LSD1/CoREST can bind to a hexapeptide derived from the SNAIL sequence through recognition of a positively charged α-helical turn that forms upon binding to the enzyme. Variations in sequence and length of this six amino acid ligand modulate affinities enabling the same binding site to differentially interact with proteins that exert distinct biological functions. The discovered short peptide inhibitors exhibit antiproliferative activities and lay the foundation for the development of peptidomimetic small molecule inhibitors of LSD1.

Regulation of myocardial interleukin-6 expression by p53 and STAT1.

Cardiovascular diseases are a major cause of morbidity and mortality worldwide. The interferon inducible transcriptional activator signal transducer and activator of transcription-1 (STAT1) and p53 are two critical transcriptional factors that have pivotal roles in cardiac biology and pathology. Here we describe a novel interplay between these two key players that critically regulate the levels of the pleiotropic interleukin 6 (IL6) in the heart. We provide in vivo evidence to demonstrate that, in cardiac tissues, STAT1 is a positive regulator of IL6 expression and it competes with the suppressive effect of p53 to sustain basal IL6 levels. Induction of IL6 expression in response to interferon gamma (IFNγ), a well-characterized activator of STAT1, parallels that of STAT1 phosphorylation and induction of STAT1 target genes, such as the interferon regulatory factor-1 (IRF-1), major histocompatibility complex class II transactivator (C2ta), and ß2-microglobulin (B2m). Furthermore, hearts from STAT1 knockout mice fail to induce IL6 expression in response to IFNγ. More importantly, we showed that this regulatory system is not functional in mouse embryonic fibroblasts, suggesting that activation of IL6 expression by STAT1 may be tissue specific. IL6 is a major effector of inflammation and cardiac hypertrophy, two major processes involved in heart failure, and therefore, understanding the molecular mechanisms regulating IL6 expression will enable better therapies and treatments for cardiovascular disease patients.

Role of STAT1 in the breast.

Signal transducer and activator of transcription-1 (STAT1) plays a role in the transduction of stress and cytokine responses, DNA damage, and activation of B and T cell immune responses. The ability of STAT1 to act as a pro- or anti-apoptotic signaling molecule depends upon the cellular environment and stimulus. Post-translational modifications provide the main method of control over the function of STAT1, however, recent data in the breast has shown that loss of STAT1 from both the tumor and the surrounding mammary epithelium greatly influence the development and response to treatment of breast cancers. Here, we discuss the recent findings of Chan et al. in Breast Cancer Research who described a new role for STAT1 in the development of estrogen receptor (ER)-positive and progesterone receptor (PR)-positive luminal breast cancers.

Family friction as ΔNp73 antagonises p73 and p53.

p53 and its homolog p73 are responsible for guarding the genome and regulating cellular responses to genotoxic damage. However, life is never simple and in fact multiple isoforms of each gene exist which may have opposing functions. ΔNp73 is a truncated isoform of p73 which lacks the N-terminal transactivation domain and is up-regulated in a number of diverse primary tumour types. Although its exact cellular function is unclear, upregulation of ΔNp73 has been linked to various pro-tumour activities. Here we review the current literature surrounding this mysterious protein and reveal its potentially important functions in tumourigenesis and treatment resistance.

Histone Deacetylase inhibitors: new promise in the treatment of immune and inflammatory diseases.

The development of Histone Deacetylase (HDAC) inhibitors has, until recently, principally been driven by their potential as anti-cancer agents. However, there is emerging evidence that HDAC inhibitors could have utility in the treatment of chronic immune and inflammatory disorders, including rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, airway hyperresponsiveness and organ transplant rejection. Here we discuss the merits of various, structurally-distinct HDAC inhibitors as potential anti-inflammatory therapeutics and provide examples of the novel medicinal chemistry approaches being undertaken to realize HDAC as a druggable target in this clinical setting.

Regulating the genome surveillance system: miRNAs and the p53 super family.

The p53 gene super family consists of three members; TP53, TP63 and TP73, encoding proteins p53, p63 and p73. Whilst p63 appears to have an essential role in embryonic development with a less clear role in carcinogenesis, irregularities in p53 and p73 signalling are implicated in tumour formation. As such, p53 is a tumour suppressor which is mutated in over 50% cancers and p73 was recently formally classified as a tumour suppressor based on data showing p73 deficient mice generate spontaneous tumours similar to those observed in p53 null mice. Dysregulation of both p53 and p73 has been correlated with cancer progression in many cell types and although mutation of these genes is often observed, some form of p53/p73 deregulation likely occurs in all tumour cells. The discovery that complementary micro RNAs (miRNAs) are able to target both of these genes provides a potential new means of perturbing p53/p73 signalling networks in cancer cells. Here we summarise the current literature regarding the involvement of miRNAs in the modulation of p53 family proteins and cancer development and detail the use of in silico methods to reveal key miRNA targets.

Functional interaction between Epstein-Barr virus replication protein Zta and host DNA damage response protein 53BP1.

Epstein-Barr virus (EBV; human herpesvirus 4) poses major clinical problems worldwide. Following primary infection, EBV enters a form of long-lived latency in B lymphocytes, expressing few viral genes, and it persists for the lifetime of the host with sporadic bursts of viral replication. The switch between latency and replication is governed by the action of a multifunctional viral protein Zta (also called BZLF1, ZEBRA, and Z). Using a global proteomic approach, we identified a host DNA damage repair protein that specifically interacts with Zta: 53BP1. 53BP1 is intimately connected with the ATM signal transduction pathway, which is activated during EBV replication. The interaction of 53BP1 with Zta requires the C-terminal ends of both proteins. A series of Zta mutants that show a wild-type ability to perform basic functions of Zta, such as dimer formation, interaction with DNA, and the transactivation of viral genes, were shown to have lost the ability to induce the viral lytic cycle. Each of these mutants also is compromised in the C-terminal region for interaction with 53BP1. In addition, the knockdown of 53BP1 expression reduced viral replication, suggesting that the association between Zta and 53BP1 is involved in the viral replication cycle.

Mechanisms of action and clinical implications of cardiac urocortin: a journey from the heart to the systemic circulation, with a stopover in the mitochondria.

The small peptide urocortin (Ucn) has the ability to protect the heart by reducing cardiac cell loss during myocardial ischemia/reperfusion, and improving post-ischemic cardiac performance. Although its mechanism of action is not clearly defined, investigations have revealed that Ucn acts through several kinase pathways, and modulates a group of genes which synergistically minimize mitochondrial damage. Besides cardioprotection, most recent findings suggest a role for Ucn as a cardiac biomarker. Serum Ucn levels may be clinically useful to diagnose cases of mild sub-lethal ischemia, lacking elevation of cardiac enzymes and electrocardiogram changes. Infusion of Ucn may also help reduce the extent of the iatrogenic ischemic/reperfusion injury, associated with cardioplegic arrest.