How to Navigate Trainee-Mentor Relationships and Interpersonal Dynamics in the Lab.

Relationships with mentors and labmates are defining aspects of a researcher's journey in science. Ideally, these interactions are outstanding opportunities to learn from others and provide the basis for lifelong collaborations. Unfortunately, sometimes interpersonal dynamics in the lab are challenging.

How to Conduct Responsible Research: A Guide for Graduate Students.

Researchers must conduct research responsibly for it to have an impact and to safeguard trust in science. Essential responsibilities of researchers include using rigorous, reproducible research methods, reporting findings in a trustworthy manner, and giving the researchers who contributed appropriate authorship credit. This "how-to" guide covers strategies and practices for doing reproducible research and being a responsible author.

Evaluating the therapeutic potential of ADAR1 inhibition for triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the deadliest form of breast cancer. Unlike other types of breast cancer that can be effectively treated by targeted therapies, no such targeted therapy exists for all TNBC patients. The ADAR1 enzyme carries out A-to-I editing of RNA to prevent sensing of endogenous double-stranded RNAs.

The snoRNA target of t(4;14) in multiple myeloma regulates ribosome biogenesis.

The orphan small nucleolar RNA (snoRNA) ACA11 is overexpressed as a result of the t(4;14) chromosomal translocation in multiple myeloma (MM), increases reactive oxygen species, and drives cell proliferation. Like other snoRNAs, ACA11 is predominantly localized to a sub-nuclear organelle, the nucleolus. We hypothesized that increased ACA11 expression would increase ribosome biogenesis and protein synthesis.

Acetate Promotes T Cell Effector Function during Glucose Restriction.

Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth.

The Role of RNA Editing in Cancer Development and Metabolic Disorders.

Numerous human diseases arise from alterations of genetic information, most notably DNA mutations. Thought to be merely the intermediate between DNA and protein, changes in RNA sequence were an afterthought until the discovery of RNA editing 30 years ago. RNA editing alters RNA sequence without altering the sequence or integrity of genomic DNA.

Sabotaging of the oxidative stress response by an oncogenic noncoding RNA.

Overexpression of the multiple myeloma set domain (MMSET) Wolf-Hirschhorn syndrome candidate 1 gene, which contains an orphan box H/ACA class small nucleolar RNA, ACA11, in an intron, is associated with several cancer types, including multiple myeloma (MM). ACA11 and MMSET are overexpressed cotranscriptionally as a result of the t(4;14) chromosomal translocation in a subset of patients with MM. RNA sequencing of CD138 tumor cells from t(4;14)-positive and -negative MM patient bone marrow samples revealed an enhanced oxidative phosphorylation mRNA signature.

Deficiency of the adaptor protein SLy1 results in a natural killer cell ribosomopathy affecting tumor clearance.

Individuals with robust natural killer (NK) cell function incur lower rates of malignancies. To expand our understanding of genetic factors contributing to this phenomenon, we analyzed NK cells from cancer resistant and susceptible strains of mice. We identified a correlation between NK levels of the X-chromosome-located adaptor protein SLy1 and immunologic susceptibility to cancer.

Targeting PTEN-defined breast cancers with a one-two punch.

With tremendous advances in sequencing and analysis in recent years, a wealth of genetic information has become available to identify and classify breast cancer into five main subtypes - luminal A, luminal B, claudin-low, human epidermal growth factor receptor 2-enriched, and basal-like. Current treatment decisions are often based on these classifications, and while more beneficial than any single treatment for all breast cancers, targeted therapeutics have exhibited limited success with most of the subtypes. Luminal B breast cancers are associated with early relapse following endocrine therapy and often exhibit a poor prognosis that is similar to that of the aggressive basal-like breast cancers.

ARF and p53 coordinate tumor suppression of an oncogenic IFN-β-STAT1-ISG15 signaling axis.

The ARF and p53 tumor suppressors are thought to act in a linear pathway to prevent cellular transformation in response to various oncogenic signals. Here, we show that loss of p53 leads to an increase in ARF protein levels, which function to limit the proliferation and tumorigenicity of p53-deficient cells by inhibiting an IFN-β-STAT1-ISG15 signaling axis. Human triple-negative breast cancer (TNBC) tumor samples with coinactivation of p53 and ARF exhibit high expression of both STAT1 and ISG15, and TNBC cell lines are sensitive to STAT1 depletion.

ARF tumor suppression in the nucleolus.

Since its discovery close to twenty years ago, the ARF tumor suppressor has played a pivotal role in the field of cancer biology. Elucidating ARF's basal physiological function in the cell has been the focal interest of numerous laboratories throughout the world for many years. Our current understanding of ARF is constantly evolving to include novel frameworks for conceptualizing the regulation of this critical tumor suppressor.

Posttranscriptional control of T cell effector function by aerobic glycolysis.

A "switch" from oxidative phosphorylation (OXPHOS) to aerobic glycolysis is a hallmark of T cell activation and is thought to be required to meet the metabolic demands of proliferation. However, why proliferating cells adopt this less efficient metabolism, especially in an oxygen-replete environment, remains incompletely understood. We show here that aerobic glycolysis is specifically required for effector function in T cells but that this pathway is not necessary for proliferation or survival.

Cathepsin K-Cre causes unexpected germline deletion of genes in mice.

Osteoclasts are terminally differentiated cells that attach to bone and secrete proteases to degrade the bone matrix. The primary protease responsible for the degradation of the organic component of the bone matrix is Cathepsin K, which was largely thought to be unique to osteoclasts. Given its apparent selective expression in osteoclasts, the Cathepsin K promoter has been engineered to drive the expression of Cre recombinase in mice and has been the most relevant tool for generating osteoclast-specific gene loss.

Multiple myeloma-associated chromosomal translocation activates orphan snoRNA ACA11 to suppress oxidative stress.

The histone methyltransferase WHSC1 (also known as MMSET) is overexpressed in multiple myeloma (MM) as a result of the t(4;14) chromosomal translocation and in a broad variety of other cancers by unclear mechanisms. Overexpression of WHSC1 did not transform wild-type or tumor-prone primary hematopoietic cells. We found that ACA11, an orphan box H/ACA class small nucleolar RNA (snoRNA) encoded within an intron of WHSC1, was highly expressed in t(4;14)-positive MM and other cancers.

Nucleophosmin redistribution following heat shock: a role in heat-induced radiosensitization.

Cellular survival from radiation-induced DNA damage requires access to sites of damage for the assembly of repair complexes and the subsequent repair, particularly the repair of DNA double strand breaks (DSB). Hyperthermia causes changes in protein-protein/DNA interactions in the nucleus that block access to sites of DNA damage. Studies presented here indicate that the nucleolar protein, nucleophosmin (NPM), redistributes from the nucleolus following hyperthermia, increases its association with DNA, and blocks access to DNA DSBs.

Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome.

Nucleophosmin (NPM) (B23) is an essential protein in mouse development and cell growth; however, it has been assigned numerous roles in very diverse cellular processes. Here, we present a unified mechanism for NPM's role in cell growth; NPM directs the nuclear export of both 40S and 60S ribosomal subunits. NPM interacts with rRNA and large and small ribosomal subunit proteins and also colocalizes with large and small ribosomal subunit proteins in the nucleolus, nucleus, and cytoplasm.

A non-tumor suppressor role for basal p19ARF in maintaining nucleolar structure and function.

The nucleolus is the center of ribosome synthesis, with the nucleophosmin (NPM) and p19(ARF) proteins antagonizing one another to either promote or inhibit growth. However, basal NPM and ARF proteins form nucleolar complexes whose functions remain unknown. Nucleoli from Arf(-/)(-) cells displayed increased nucleolar area, suggesting that basal ARF might regulate key nucleolar functions.

Therapeutic targets in the ARF tumor suppressor pathway.

One of the outstanding fundamental questions in cancer cell biology concerns how cells coordinate cellular growth (or macromolecular synthesis) with cell cycle progression and mitosis. Intuitively, rapidly dividing cells must have some control over these processes; otherwise cells would continue to shrink in volume with every passing cycle, similar to the cytoreductive divisions seen in the very early stages of embryogenesis. The problem is easily solved in unicellular organisms, such as yeast, as their growth rates are entirely dependent on nutrient availability.

TSC1 sets the rate of ribosome export and protein synthesis through nucleophosmin translation.

Nucleophosmin (B23) is a nucleolar phosphoprotein that has been implicated in numerous cellular processes. In particular, nucleophosmin interacts with nucleolar components of newly synthesized ribosomes to promote ribosome nuclear export. Nucleophosmin is a classic mitogen-induced protein, with changes in its expression correlating with growth factor stimulation.

Role of MAPK in the regulation of double-stranded RNA- and encephalomyocarditis virus-induced cyclooxygenase-2 expression by macrophages.

In response to virus infection or treatment with dsRNA, macrophages express the inducible form of cyclooxygenase-2 (COX-2) and produce proinflammatory prostaglandins. Recently, we have shown that NF-kappaB is required for encephalomyocarditis virus (EMCV)- and dsRNA-stimulated COX-2 expression in mouse macrophages. The dsRNA-dependent protein kinase R is not required for EMCV-stimulated COX-2 expression, suggesting the presence of protein kinase R-independent pathways in the regulation of this antiviral gene.

Nucleophosmin is essential for ribosomal protein L5 nuclear export.

Nucleophosmin (NPM/B23) is a key regulator in the regulation of a number of processes including centrosome duplication, maintenance of genomic integrity, and ribosome biogenesis. While the mechanisms underlying NPM function are largely uncharacterized, NPM loss results in severe dysregulation of developmental and growth-related events. We show that NPM utilizes a conserved CRM1-dependent nuclear export sequence in its amino terminus to enable its shuttling between the nucleolus/nucleus and cytoplasm.