Dataset Information

Post-translational control of the long and winding road to cholesterol.

ABSTRACT: The synthesis of cholesterol requires more than 20 enzymes, many of which are intricately regulated. Post-translational control of these enzymes provides a rapid means for modifying flux through the pathway. So far, several enzymes have been shown to be rapidly degraded through the ubiquitin-proteasome pathway in response to cholesterol and other sterol intermediates. Additionally, several enzymes have their activity altered through phosphorylation mechanisms. Most work has focused on the two rate-limiting enzymes: 3-hydroxy-3-methylglutaryl CoA reductase and squalene monooxygenase. Here, we review current literature in the area to define some common themes in the regulation of the entire cholesterol synthesis pathway. We highlight the rich variety of inputs controlling each enzyme, discuss the interplay that exists between regulatory mechanisms, and summarize findings that reveal an intricately coordinated network of regulation along the cholesterol synthesis pathway. We provide a roadmap for future research into the post-translational control of cholesterol synthesis, and no doubt the road ahead will reveal further twists and turns for this fascinating pathway crucial for human health and disease.

SUBMITTER: Sharpe LJ

PROVIDER: S-EPMC7762936 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Post-translational control of the long and winding road to cholesterol.

Sharpe Laura J LJ Coates Hudson W HW Brown Andrew J AJ

The Journal of biological chemistry 20201201 51

The synthesis of cholesterol requires more than 20 enzymes, many of which are intricately regulated. Post-translational control of these enzymes provides a rapid means for modifying flux through the pathway. So far, several enzymes have been shown to be rapidly degraded through the ubiquitin-proteasome pathway in response to cholesterol and other sterol intermediates. Additionally, several enzymes have their activity altered through phosphorylation mechanisms. Most work has focused on the two ra ...[more]

PMID: 33453997

Similar Datasets

Project description:BackgroundDespite a remarkable increase in the depth of our understanding and management of breast cancer in the past 50 years, the disease is still a major public health problem worldwide and poses significant challenges. The palpability of breast tumors has facilitated diagnosis and documentation since ancient times. The earliest descriptions of breast cancer date back to around 3500 BCE. For centuries to follow, theories by Hippocrates (460 BCE) and Galen (200 CE), attributing the cause of breast cancer to an "excess of black bile" and treatment options including the use of opium and castor oil, prevailed. Surgical resection was introduced in the 18th century. The advent of modern medicine led to the development of novel treatment options that include hormonal, targeted and chemo-therapies. There are still several therapeutic challenges including the treatment of triple negative breast cancer (TNBC), and overcoming drug resistance.Scope of reviewThe increased incidence and awareness of breast cancer has led to significant changes in diagnosis and treatment in recent decades. But, mankind has come a long way. Herein, I have traced how our understanding of breast cancer has evolved from the early description of the disease around 460 BCE as "black bile-containing crab-like tumors" to the conventional as a heterogeneous disease with high degree of diversity between and within tumors, as well as among breast cancer patients. How is breast cancer treated today and how do risk factors, breast cancer subtype and drug resistance contribute to the therapeutic challenges at the turn of the 21st century?Major conclusionsBreast cancer remains a serious public health issue worldwide. However, appreciable growth in our understanding of breast cancer in the past century has led to remarkable progress in the early detection, treatment and prevention of the disease. The clinical focus is shifting more towards tailored therapy as more targets are characterized and novel highly innovative approaches are developed.General significanceTracing the history of breast cancer, highlights how increased awareness of the disease, and progress in research and development have enhance our understanding of the disease.

Project description:BACKGROUND: Years of advocacy for the neglected tropical diseases (NTDs) have focused the world's attention on these diseases of the poor, resulting most recently in the 2012 "London Declaration" and the recent World Health Assembly Resolution WHA66.12 on NTDs in May 2013. Control of the endemic neglected zoonotic diseases (NZDs) would benefit from a similar campaign, which needs the support of a global community. METHODOLOGY/PRINCIPAL FINDINGS: The resolutions from all 66 World Health Assembly (WHA) meetings held between 1948 and 2013 were examined to determine how many contain a specific focus on any of the following eight NZDs as defined by the World Health Organisation (WHO): anthrax, bovine tuberculosis (TB), brucellosis, Taenia solium cysticercosis, cystic echinococcosis (hydatidosis), leishmaniasis, rabies, and zoonotic human African trypanosomiasis (HAT or sleeping sickness). Twenty-one resolutions adopted in the 16 assemblies between 1948 and 2013 targeted one or more of these eight NZDs, representing 4% of the total resolutions on infectious diseases passed to date. The 2013 adoption of Resolution WHA66.12 targeting all 17 NTDs marks a change in approach by the WHA. Whereas previous resolutions have targeted the NTDs as separate entities, the new approach of the combined resolution will help increase the overall momentum to target these ancient diseases as coendemic clusters in endemic countries. However, three major NZDs remain outside this recent resolution: anthrax, brucellosis, and bovine TB. CONCLUSIONS AND SIGNIFICANCE: The recent adoption of a specific resolution at the WHA in 2013 that emphasises a One Health approach for the successful control of 17 NTDs is a major development in advocacy. However, recognition of the importance of three major NZDs to public health in endemic countries-anthrax, brucellosis, and bovine tuberculosis-is still lacking despite being prioritised by the WHA as early as the 1950s. Global advocacy for control of the NZDs as a whole would similarly benefit from adoption of a One Health approach as is promoted for the NTDs under WHA66.12.

Project description:Background and objectivesMany dementia caregivers provide care for numerous years. Exhibiting grit, or commitment and persistence in the face of adversity, may bolster their ability to manage caregiving challenges. We explored grit in relationship to memory and behavior problems and response to stressors among women engaged in long-term dementia care.Research design and methodsInformed by a life course perspective, and guided by stress-process theory, we interviewed 10 women with a spouse or parent initially diagnosed with mild cognitive impairment 4 times over 10 years. Using Charmaz's analysis methods and grit as a sensitizing concept, we employed an unfolding analytic strategy involving (a) thematic analysis to identify expressions of grit in response to caregiving stressors across interviews and (b) case-by-case comparisons to assess associations of grit with the use of care strategies across caregivers over time.ResultsDementia caregivers experienced unrelenting and changing psychosocial and physical challenges. Over time, most women exhibited a sustained commitment to the relationship through the ways in which they protected the identity of the person with dementia, modified their expectations for emotional intimacy, and managed their financial affairs. They persevered as their roles and relationships fluctuated, often finding purpose and relief through employment and leisure pursuits. As care intensified, women who took charge and consciously made decisions in the best interest of the care recipient and themselves minimized stress.Discussion and implicationsWhile some caregivers exhibited grit from the outset, all showed enhanced perseverance and commitment to the ways they managed memory-related changes over time. Developing confidence in their ability to manage and provide care helped the caregivers respond to stressors with purpose and sustain their roles and responsibilities. Enhancing grit in long-term dementia caregivers may result in better individual and relational outcomes.

Project description:Studies in our laboratory over the last three decades have shown that the Chinese hamster dihydrofolate reductase (DHFR) origin of replication corresponds to a broad zone of inefficient initiation sites distributed throughout the spacer between the convergently transcribed DHFR and 2BE2121 genes. It is clear from mutational analysis that none of these sites is genetically required for controlling origin activity. However, the integrity of the promoter of the DHFR gene is needed to activate the downstream origin, while the 3' processing signals prevent invasion and inactivation of the downstream origin by transcription forks. Several other origins in metazoans have been shown to correspond to zones of inefficient sites, while a different subset appears to be similar to the fixed replicators that characterize origins in S. cerevisiae and lower organisms. These observations have led us to suggest a model in which the mammalian genome is dotted with a hierarchy of degenerate, redundant, and inefficient replicators at intervals of a kilobase or less, some of which may have evolved to be highly circumscribed and efficient. The activities of initiation sites are proposed to be largely regulated by local transcription and chromatin architecture. Recently, we and others have devised strategies for identifying active origins on a genome-wide scale in order to define their distributions between fixed and dispersive origin types and to detect relationships among origins, genes, and epigenetic markers. The global pictures emerging are suggestive but far from complete and appear to be plagued by some of the same uncertainties that have led to conflicting views of individual origins in the past (particularly DHFR). In this paper, we will trace the history of origin discovery in mammalian genomes, primarily using the well-studied DHFR origin as a model, because it has been analyzed by nearly every available origin mapping technique in several different laboratories, while many origins have been identified by only one. We will address the strengths and shortcomings of the various methods utilized to identify and characterize origins in complex genomes and will point out how we and others were sometimes led astray by false assumptions and biases, as well as insufficient information. The goal is to help guide future experiments that will provide a truly comprehensive and accurate portrait of origins and their regulation. After all, in the words of George Santayana, "Those who do not learn from history are doomed to repeat it."

Dataset Information

Post-translational control of the long and winding road to cholesterol.

Publications

Post-translational control of the long and winding road to cholesterol.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets