Dr. Troy Harkness’ lab at the University of Saskatchewan, in the Department of Anatomy and Cell Biology, has used funds provided by the CIHR Institute of Aging to advance our knowledge of how cells age using budding yeast as a model…
The Canadian Institute for Health Research (CIHR) provides funding for a broad array of research across Canada, ranging from patient oriented research to curiosity driven science using a diverse variety of model systems including bacteria, yeast, worms and flies. With the idea in mind that DNA maintenance is the most critical event in a cell’s life, it becomes apparent that knowledge gained from simple model systems, such as yeast, can be directly applied to human health. This idea is forged by the fact that cancer arises when DNA stability goes awry and that basic heredity is grounded in the passage of perfect copies of the genome from mother to daughter. At the molecular level, yeast and humans are very similar, with upwards of 50% of human genes conserved with their yeast counterpart. The conserved molecular and genetic nature of yeast and human cells has allowed yeast to be used extensively to study the molecular genetics of cancer and aging. Strikingly, the first genes isolated that influenced yeast aging are functionally conserved all the way to mice, and in some cases, predicted to apply to humans as well (1).
Dr. Troy Harkness’ lab at the University of Saskatchewan, in the Department of Anatomy and Cell Biology, has used funds provided by the CIHR Institute of Aging to advance our knowledge of how cells age using budding yeast as a model. Over the past 2 decades it has been clear that sugar metabolism and the stress response play opposed roles in controlling cell proliferation and protecting the cell from damage. The insulin-signalling pathway in multicellular organisms is at the nexus of growth and repair. When the equilibrium of the pathway is altered, uncontrolled proliferation (cancer), or increased stress response (increased cell health), will result. However, studying signalling pathways at the molecular and genetic level in animal systems is very difficult, limiting what we can learn about how to control ageing and cancer. The effects on cell health and stress response are what tweaked researchers to the fact that yeast ageing can be genetically controlled; increased cell health directly leads to increased lifespan. The budding, or more commonly, baking or brewing yeast, does not respond to insulin, but nonetheless encodes intracellular components of the insulin-signalling pathway. This is because yeast cells respond directly to sugars in the environment and do not need insulin to tell them food is available. The Harkness’ lab first foray into ageing studies was the result of identifying a critical modulator of cell cycle progression that could directly control yeast lifespan; the Anaphase Promoting Complex (APC), a large multi-subunit conserved protein complex, targets proteins that inhibit mitotic progression for ubiquitin-dependent protein degradation, and when defective, yeast lifespan is decreased, but lifespan is increased when the APC subunits are overexpressed (2). Studies have shown that conserved factors in cells, from yeast to humans that inhibit the insulin-signalling pathway, particularly the AMP-dependent kinase (AMPK in humans, SNF1 in yeast), halt cell growth in the presence of stress, leading to increased yeast lifespan (2-4).
With this knowledge, Harkness then turned to his colleague, Dr. Terra Arnason, a Clinician Scientist in the Division of Endocrinology at the University of Saskatchewan, who uses yeast to study metabolic disorders such as diabetes. The Arnason lab has shown that the yeast AMP-dependent kinase, SNF1, is regulated through its Ubiquitin-Associated (UBA) domain (3). This novel observation was coupled with their discovery that SNF1 activity was driven by the stress response Forkhead Box (FOX) transcription factors Fkh1 and Fkh2 and together impacted stress resistance and ageing control. The FOX family members, which are highly conserved from yeast to humans, play an important role in extending lifespan in a variety of organisms (5). The Harkness lab was the first to show that Fkh1 and Fkh2 control yeast aging and that this occurs in collaboration with the APC (6-8). In human cells, it is known that AMPK and FOXO proteins respond to stress, as in yeast, but how they interact remains elusive. Also, AMPK and the FOXOs play a negative role in insulin-signalling, the basics of which are clear, but fine detail is still lacking. The collaborative work proposed by the Arnason and Harkness labs using yeast provides the opportunity to extend what we know about how cancer and ageing pathways in humans can be fine-tuned, with the potential of identifying novel druggable targets. With the generous assistance of CIHR, this research will lead the way to understanding the fine details governing how stress response pathways can increase the health of a cell, ultimately lead to better health and longevity of the organism.
References
1. Pitt JN, Kaeberlein M. (2015. Why is aging conserved and what can we do about it? PLoS Biol. 13:e1002131.
2. Harkness TA, Shea KA, Legrand C, Brahmania M, Davies GF. 2004. A functional analysis reveals dependence on the anaphase-promoting complex for prolonged life span in yeast. Genetics 168:759-74.
3. Jiao R, Postnikoff S, Harkness TA, Arnason TG. 2015. The SNF1 Kinase Ubiquitin-associated Domain Restrains Its Activation, Activity, and the Yeast Life Span. J Biol Chem. 290:15393-404.
4. Yao Y, Tsuchiyama S, Yang C, Bulteau AL, He C, et al. 2015. Proteasomes, Sir2, and Hxk2 form an interconnected aging network that impinges on the AMPK/Snf1-regulated transcriptional repressor Mig1. PLoS Genet. 11:e1004968.
5. Martins R, Lithgow GJ, Link W. 2016. Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell 15:196-207.
7. Postnikoff SD, Harkness TA. 2012. Mechanistic insights into aging, cell-cycle progression, and stress response. Front Physiol. 3:183.
8. Postnikoff SD, Malo ME, Wong B, Harkness TA. 2012. The yeast forkhead transcription factors fkh1 and fkh2 regulate lifespan and stress response together with the anaphase-promoting complex. PLoS Genet. 8:e1002583.
Dr. Troy Harkness
troy.harkness@usask.ca
Dr. Terra Arnason
terra.arnason@usask.ca
University of Saskatchewan
http://medicine.usask.ca/department/schools-divisions/biomed/acb.php
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