Andrew P. Dennis

Bio: Andrew P. Dennis is an academic researcher from Baylor College of Medicine. The author has contributed to research in topics: Receptor & Proteasome inhibitor. The author has an hindex of 5, co-authored 6 publications receiving 915 citations.

Proteasome-dependent degradation of the human estrogen receptor

Abstract: In eukaryotic cells, the ubiquitin–proteasome pathway is the major mechanism for the targeted degradation of proteins with short half-lives. The covalent attachment of ubiquitin to lysine residues of targeted proteins is a signal for the recognition and rapid degradation by the proteasome, a large multi-subunit protease. In this report, we demonstrate that the human estrogen receptor (ER) protein is rapidly degraded in mammalian cells in an estradiol-dependent manner. The treatment of mammalian cells with the proteasome inhibitor MG132 inhibits activity of the proteasome and blocks ER degradation, suggesting that ER protein is turned over through the ubiquitin–proteasome pathway. In addition, we show that in vitro ER degradation depends on ubiquitin-activating E1 enzyme (UBA) and ubiquitin-conjugating E2 enzymes (UBCs), and the proteasome inhibitors MG132 and lactacystin block ER protein degradation in vitro. Furthermore, the UBA/UBCs and proteasome inhibitors promote the accumulation of higher molecular weight forms of ER. The UBA and UBCs, which promote ER degradation in vitro, have no significant effect on human progesterone receptor and human thyroid hormone receptor β proteins.

Importance of the regulation of nuclear receptor degradation.

Abstract: Nuclear hormone receptors (NHRs) represent a superfamily of structurally related ligand-activated transcription factors, which regulate diverse biological activities like growth, development, and homeostasis. Recently, it has been demonstrated that certain members of the NHR superfamily are degraded through the ubiquitin-proteasome pathway in a ligand-dependent manner. Though the signal for the down-regulation via the ubiquitin-proteasome pathway is not yet known, phosphorylation at specific amino acid residues or coactivator binding to receptors could lead to their degradation by the 26S proteasome. Activation and degradation seems to be an engineered cyclic mechanism, which provides tight control over diverse cellular processes. The degradation process involves extensive loss of proteins and requires expenditure of cellular ATP. That seems to be inevitable for a more important aim, that is efficient and appropriate regulation of transcription. Down-regulation of receptors would lead to an attenuated transcriptional response because the number of receptor molecules available to activate transcription would decrease over time. One of the obvious reasons for down-regulating NHRs thus seems to be to prevent the cell from overstimulation by the hormones or other activating signals. Nuclear receptor turnover may also reset the transcriptional apparatus in preparation for a subsequent response. Since inhibition of the ubiquitin-proteasome degradation pathway disturbs the transcriptional activitity of some of the nuclear receptors such as estrogen (ER) and progesterone (PR) receptors, it is also possible that the degradation of NHRs may enable recycling of components of receptor-cofactor complexes and general transcriptional machinary. Understanding the mechanism of nuclear hormone receptor degradation and its relation to transcription may lead to novel insights of therapuetic intervention.

Hormones and endocrine-disrupting chemicals: Low-dose effects and nonmonotonic dose responses

Abstract: For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from...

Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response.

Abstract: A decade of intensive investigation of coactivators and corepressors required for regulated actions of DNA-binding transcription factors has revealed a network of sequentially exchanged cofactor complexes that execute a series of enzymatic modifications required for regulated gene expression. These coregulator complexes possess “sensing” activities required for interpretation of multiple signaling pathways. In this review, we examine recent progress in understanding the functional consequences of “molecular sensor” and “molecular adaptor” actions of corepressor/coactivator complexes in integrating signal-dependent programs of transcriptional responses at the molecular level. This strategy imposes a temporal order for modifying programs of transcriptional regulation in response to the cellular milieu, which is used to mediate developmental/homeostatic and pathological events.

Long Noncoding RNAs

Abstract: Genetic information in most living organisms on Earth is stored in the form of a chemical structure, known as deoxyribonucleic acid (DNA). Researchers discovered that pieces of long DNA molecules, called genes, are recognized by the nuclear multi-subunit complex of ribonucleic acid (RNA) polymerase, which then produces molecules of RNA, complementarily mirroring the original DNA. Some of these RNA molecules carry information that can be used to produce polypeptide chains with pre-defi ned amino acid sequences. These molecules have been named messenger RNAs (mRNAs). Others, such as ribosomal RNAs, transfer RNAs, and small nuclear RNAs, have been found to drive and regulate production of proteins. They are sometimes referred to as housekeeping or structural RNAs. However, sequences of mRNAs together with structural RNAs account for less than 10 % of animal and plant genomes. The rest of the genome was considered silent and non-functional, until on-going research revealed that about 80 % of DNA might be transcribed, producing numerous long noncoding RNA molecules with important functions. This chapter gives an overview of mammalian transcriptome research in recent decades. It discusses the main technology platforms, comparing their strong sides and disadvantages. Some of the most important fi ndings are summarized, with an overview of the future prospectives in long noncoding RNA research. The chapter shows that the current understanding of what is a gene should be revised, in order to clearly defi ne the complex relationship between product-coding regions, regulatory sequences, and the organism’s phenotype.