Robert N. Eisenman

OBJECTIVES: Specific changes in the functional connectivity of brain networks occur in patients with epilepsy. Yet whether such changes reflect a stable disease effect or one that is a function of active seizure burden remains unclear. Here, we longitudinally assessed the connectivity of canonical cognitive functional networks in patients with intractable temporal lobe epilepsy (TLE), both before and after patients underwent epilepsy surgery and achieved seizure freedom. METHODS: Seventeen patients with intractable TLE who underwent epilepsy surgery with Engel class I outcome and 17 matched healthy controls took part in the study...

Myc plays critical roles in the self-renewal division of various stem cell types. In spermatogonial stem cells (SSCs), Myc controls SSC fate decisions because Myc overexpression induces enhanced self-renewal division, while depletion of Max, a Myc-binding partner, leads to meiotic induction. However, the mechanism by which Myc acts on SSC fate is unclear. Here we demonstrate a critical link between Myc/Mycn gene activity and glycolysis in SSC self-renewal. In SSCs, Myc/Mycn are regulated by Foxo1, whose deficiency impairs SSC self-renewal...

The balance between metabolism and biomass is very important in biological systems; however, to date there has been no quantitative method to characterize the balance. In this methodological study, we propose to use the distribution of amino acids in different domains to investigate this balance. It is well known that endogenous or exogenous amino acids in a biological system are either metabolized or incorporated into free amino acids (FAAs) or proteome amino acids (PAAs). Using glycine (Gly) as an example, we demonstrate a novel method to accurately determine the amounts of amino acids in various domains using serum, urine, and cell samples...

MYC-nick is a cytoplasmic, transcriptionally inactive member of the MYC oncoprotein family, generated by a proteolytic cleavage of full-length MYC. MYC-nick promotes migration and survival of cells in response to chemotherapeutic agents or withdrawal of glucose. Here we report that MYC-nick is abundant in colonic and intestinal tumors derived from mouse models with mutations in the Wnt, TGF-β, and PI3K pathways. Moreover, MYC-nick is elevated in colon cancer cells deleted for FBWX7, which encodes the major E3 ligase of full-length MYC frequently mutated in colorectal cancers...

Small cell lung cancer (SCLC) is a devastating neuroendocrine carcinoma. MYCL (L-Myc) is frequently amplified in human SCLC, but its roles in SCLC progression are poorly understood. We isolated preneoplastic neuroendocrine cells from a mouse model of SCLC and found that ectopic expression of L-Myc, c-Myc, or N-Myc conferred tumor-forming capacity. We focused on L-Myc, which promoted pre-rRNA synthesis and transcriptional programs associated with ribosomal biogenesis. Deletion of Mycl in two genetically engineered models of SCLC resulted in strong suppression of SCLC...

Mouse embryonic stem cells (ESCs) are maintained in a naive ground state of pluripotency in the presence of MEK and GSK3 inhibitors. Here, we show that ground-state ESCs express low Myc levels. Deletion of both c-myc and N-myc (dKO) or pharmacological inhibition of Myc activity strongly decreases transcription, splicing, and protein synthesis, leading to proliferation arrest. This process is reversible and occurs without affecting pluripotency, suggesting that Myc-depleted stem cells enter a state of dormancy similar to embryonic diapause...

Myc and its paralog MycN are thought to be functionally redundant, but Myc- and MycN-driven medulloblastomas exhibit distinct phenotypes. In this issue of Cancer Cell, Vo and colleagues (2016) show that this phenotypic difference stems from the preferential ability of Myc, relative to MycN, to bind Miz1 and repress transcription.

Metabolic stress and changes in nutrient levels modulate many aspects of skeletal muscle function during aging and disease. Growth factors and cytokines secreted by skeletal muscle, known as myokines, are important signaling factors, but it is largely unknown whether they modulate muscle growth and differentiation in response to nutrients. Here, we found that changes in glucose levels increase the activity of the glucose-responsive transcription factor MLX (Max-like protein X), which promotes and is necessary for myoblast fusion...

Cell-based therapies to treat retinal degeneration are now being tested in clinical trials. However, it is not known whether the source of stem cells is important for the production of differentiated cells suitable for transplantation. To test this, we generated induced pluripotent stem cells (iPSCs) from murine rod photoreceptors (r-iPSCs) and scored their ability to make retinae by using a standardized quantitative protocol called STEM-RET. We discovered that r-iPSCs more efficiently produced differentiated retinae than did embryonic stem cells (ESCs) or fibroblast-derived iPSCs (f-iPSCs)...

Amino acids play essential roles in both metabolism and the proteome. Many studies have profiled free amino acids (FAAs) or proteins; however, few have connected the measurement of FAA with individual amino acids in the proteome. In this study, we developed a metabolomics method to comprehensively analyze amino acids in different domains, using two examples of different sample types and disease models. We first examined the responses of FAAs and insoluble-proteome amino acids (IPAAs) to the Myc oncogene in Tet21N human neuroblastoma cells...

Deregulated Myc transcriptionally reprograms cell metabolism to promote neoplasia. Here we show that oncogenic Myc requires the Myc superfamily member MondoA, a nutrient-sensing transcription factor, for tumorigenesis. Knockdown of MondoA, or its dimerization partner Mlx, blocks Myc-induced reprogramming of multiple metabolic pathways, resulting in apoptosis. Identification and knockdown of genes coregulated by Myc and MondoA have allowed us to define metabolic functions required by deregulated Myc and demonstrate a critical role for lipid biosynthesis in survival of Myc-driven cancer...

The Myc proto-oncogene has been intensively studied in tumorigenesis and development. A new paper in Cell reports the role of Myc as a determinant of mammalian longevity. Myc heterozygous mice exhibit extended lifespans resulting from alterations in multiple cellular processes distinct from those observed in other longevity models.

The transcription factor MYC and its related family members MYCN and MYCL have been implicated in the etiology of a wide spectrum of human cancers. Compared to other oncoproteins, such as RAS or SRC, MYC is unique because its protein coding region is rarely mutated. Instead, MYC's oncogenic properties are unleashed by regulatory mutations leading to unconstrained high levels of expression. Under both normal and pathological conditions MYC regulates multiple aspects of cellular physiology including proliferation, differentiation, apoptosis, growth and metabolism by controlling the expression of thousands of genes...

Evasion of apoptosis is critical in Myc-induced tumor progression. Here we report that cancer cells evade death under stress by activating calpain-mediated proteolysis of Myc. This generates Myc-nick, a cytoplasmic, transcriptionally inactive cleavage product of Myc. We found conversion of Myc into Myc-nick in cell lines and tissues derived from multiple cancers. In colon cancer, the production of Myc-nick is enhanced under stress conditions such as hypoxia and nutrient deprivation. Under these conditions, ectopic expression of Myc-nick promotes anchorage-independent growth and cell survival at least in part by promoting autophagy...

This review is intended to provide a broad outline of the biological and molecular functions of MYC as well as of the larger protein network within which MYC operates. We present a view of MYC as a sensor that integrates multiple cellular signals to mediate a broad transcriptional response controlling many aspects of cell behavior. We also describe the larger transcriptional network linked to MYC with emphasis on the MXD family of MYC antagonists. Last, we discuss evidence that the network has evolved for millions of years, dating back to the emergence of animals...

The essential and highly conserved role of Myc in organismal growth and development is dependent on the control of Myc protein abundance. It is now well established that Myc levels are in part regulated by ubiquitin-dependent proteasomal degradation. Using a genetic screen for modifiers of Drosophila Myc (dMyc)-induced growth, we identified and characterized a ubiquitin-specific protease (USP), Puffyeye (Puf), as a novel regulator of dMyc levels and function in vivo. We show that puf genetically and physically interacts with dMyc and the ubiquitin ligase archipelago (ago) to modulate a dMyc-dependent cell growth phenotype, and that varying Puf levels in both the eye and wing phenocopies the effects of altered dMyc abundance...

Glioblastoma multiforme (GBM) is a clinically and pathologically heterogeneous brain tumor. Previous studies of transcriptional profiling have revealed biologically relevant GBM subtypes associated with specific mutations and dysregulated pathways. Here, we applied a modified proteome to uncover abnormal protein expression profile in a MRI-classified group I GBM (GBM1), which has a spatial relationship with one of the adult neural stem cell niches, subventricular zone (SVZ). Most importantly, we identified molecular characteristics in this type of GBM that include up-regulation of metabolic enzymes, ribosomal proteins, and heat shock proteins...

Regulation of Myc protein abundance is critical for normal cell growth as evidenced by the fact that deregulated Myc expression is a hallmark of many cancers. One of several important mechanisms that control Myc levels involves its phosphorylation-dependent proteolysis. Previous studies have shown that phosphorylation of threonine 58 by glycogen synthase kinase 3β (GSK3β) within the conserved Myc Box I sequence results in binding by the ubiquitin ligase Fbw7-SCF complex, followed by ubiquitination and proteasome-mediated degradation of Myc...

BACKGROUND: Expectations for outcomes after the neonatal arterial switch operation (ASO) continue to change. This cohort study describes neurodevelopmental outcomes at age 12 months after neonatal ASO, and analyzes both modifiable and nonmodifiable factors for association with adverse outcomes. METHODS: Patients who underwent an ASO (n=30) were enrolled in a prospective outcome study, with comprehensive clinical data collection during the first 12 months of life...

c-Myc is involved in the control of diverse cellular processes and implicated in the maintenance of different tissues including the neural crest. Here, we report that c-Myc is particularly important for pigment cell development and homeostasis. Targeting c-Myc specifically in the melanocyte lineage using the floxed allele of c-Myc and Tyr::Cre transgenic mice results in a congenital gray hair phenotype. The gray coat color is associated with a reduced number of functional melanocytes in the hair bulb and melanocyte stem cells in the hair bulge...