Sharon D. Morgenbesser

Bio: Sharon D. Morgenbesser is an academic researcher from Yeshiva University. The author has contributed to research in topics: Transcription factor & Receptor tyrosine kinase. The author has an hindex of 4, co-authored 6 publications receiving 2081 citations.

Myc family oncoproteins function through a common pathway to transform normal cells in culture: cross-interference by Max and trans-acting dominant mutants.

Abstract: The myc family of cellular oncogenes encodes three highly related nuclear phosphoproteins (c-Myc, N-Myc, and L-Myc) that are believed to function as sequence-specific transcription factors capable of regulating genes important in cellular growth and differentiation. Current evidence indicates that Myc family proteins exist as biologically active heterodimeric complexes in association with another helix-loop-helix leucine zipper phosphoprotein, Max. We have investigated the common and unique properties among the Myc family, as well as the physiological role of Max in the regulation of Myc family function. We demonstrate that trans-activation-incompetent mutants of one Myc family member can act in trans to dominantly suppress the cotransformation activities of all three Myc oncoproteins, indicating that the Myc family functions through common genetic elements in its cellular transformation pathways. Employing co-immunoprecipitation with either anti-Myc or anti-Max antibodies, we show that the transfected normal c-Myc, N-Myc, and L-Myc oncoproteins associate with the endogenous Max protein in REF transformants, indicating that the Max interaction represents at least one component common to Myc family function. In addition, we observed a striking reduction in Myc cotransformation activity when a Max expression construct was added to myc/ras co-transfections. We discuss these biological findings in the context of a proposed model for Myc/Max function and regulation in which Max serves as either an obligate partner in the Myc/Max transcriptional complex or as a repressor in the form of a transcriptionally inert Max/Max homodimer capable of occupying Myc/Max-responsive gene targets.

Expression and activity of L-Myc in normal mouse development.

Abstract: To determine the role of L-Myc in normal mammalian development and its functional relationship to other members of the Myc family, we determined the normal patterns of L-myc gene expression in the developing mouse by RNA in situ hybridization and assessed the phenotypic impact of L-Myc deficiency produced through standard gene targeting methodology. L-myc transcripts were detected in the developing kidney and lung as well as in both the proliferative and the differentiative zones of the brain and neural tube. Despite significant expression of L-myc in developing mouse tissue, homozygous null L-myc mice were found to be viable, reproductively competent, and represented in expected frequencies from heterozygous matings. A detailed histological survey of embryonic and adult tissues, characterization of an embryonic neuronal marker, and measurement of cellular proliferation in situ did not reveal any congenital abnormalities. The lack of an apparent phenotype associated with L-Myc deficiency indicates that L-Myc is dispensable for gross morphological development and argues against a unique role for L-Myc in early central nervous system development as had been previously suggested. Although overlapping expression patterns among myc family members raise the possibility of complementation of L-Myc deficiency by other Myc oncoproteins, compensatory changes in the levels of c- and/or N-myc transcripts were not detected in homozygous null L-myc mice.

Insulin signalling and the regulation of glucose and lipid metabolism

Abstract: The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide. In both disorders, tissues such as muscle, fat and liver become less responsive or resistant to insulin. This state is also linked to other common health problems, such as obesity, polycystic ovarian disease, hyperlipidaemia, hypertension and atherosclerosis. The pathophysiology of insulin resistance involves a complex network of signalling pathways, activated by the insulin receptor, which regulates intermediary metabolism and its organization in cells. But recent studies have shown that numerous other hormones and signalling events attenuate insulin action, and are important in type 2 diabetes.

Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions.

Abstract: Mitogen-activated protein (MAP) kinases comprise a family of ubiquitous proline-directed, protein-serine/threonine kinases, which participate in signal transduction pathways that control intracellular events including acute responses to hormones and major developmental changes in organisms. MAP kinases lie in protein kinase cascades. This review discusses the regulation and functions of mammalian MAP kinases. Nonenzymatic mechanisms that impact MAP kinase functions and findings from gene disruption studies are highlighted. Particular emphasis is on ERK1/2.

The MAPK signaling cascade.

Abstract: The transmission of extracellular signals into their intracellular targets is mediated by a network of interacting proteins that regulate a large number of cellular processes. Cumulative efforts from many laboratories over the past decade have allowed the elucidation of one such signaling mechanism, which involves activations of several membranal signaling molecules followed by a sequential stimulation of several cytoplasmic protein kinases collectively known as mitogen-activated protein kinase (MAPK) signaling cascade. Up to six tiers in this cascade contribute to the amplification and specificity of the transmitted signals that eventually activate several regulatory molecules in the cytoplasm and in the nucleus to initiate cellular processes such as proliferation, differentiation, and development. Moreover, because many oncogenes have been shown to encode proteins that transmit mitogenic signals upstream of this cascade, the MAPK pathway provides a simple unifying explanation for the mechanism of action...

A protein kinase involved in the regulation of inflammatory cytokine biosynthesis.

Abstract: Production of interleukin-1 and tumour necrosis factor from stimulated human monocytes is inhibited by a new series of pyridinyl-imidazole compounds. Using radiolabelled and radio-photoaffinity-labelled chemical probes, the target of these compounds was identified as a pair of closely related mitogen-activated protein kinase homologues, termed CSBPs. Binding of the pyridinyl-imidazole compounds inhibited CSBP kinase activity and could be directly correlated with their ability to inhibit cytokine production, suggesting that the CSBPs are critical for cytokine production.