RESUMO
Liquid biopsies-tests that detect circulating tumor cellular components in the bloodstream-have the potential to transform cancer by reducing health inequities in screening, diagnostics, and monitoring. Today, liquid biopsies are being used to guide treatment choices for patients and monitor for cancer recurrence, and promising work in multi-cancer early detection is ongoing. However, without awareness of the barriers to adoption of this new technology and a willingness to build mitigation efforts into the implementation of widespread liquid biopsy testing, the communities that could most benefit may be the last to access and use them. In this work, we review the challenges likely to affect the accessibility of liquid biopsies in both the general population and underserved populations, and recommend specific actions to facilitate equitable access for all patients.
Assuntos
Células Neoplásicas Circulantes , Humanos , Biópsia LíquidaRESUMO
Protein phosphorylation is an essential regulatory mechanism that controls most cellular processes, integrating a variety of environmental signals to drive cellular growth. Isr1 is a negative regulator of the hexosamine biosynthesis pathway (HBP), which produces UDP-GlcNAc, an essential carbohydrate that is the building block of N-glycosylation, GPI anchors and chitin. Isr1 was recently shown to be regulated by phosphorylation by the nutrient-responsive CDK kinase Pho85, allowing it to be targeted for degradation by the SCFCDC4. Here, we show that while deletion of PHO85 stabilizes Isr1 in asynchronous cells, Isr1 is still unstable in mitotically arrested cells in a pho85∆ strain. We provide evidence to suggest that this is through phosphorylation by CDK1. Redundant targeting of Isr1 by two distinct kinases may allow for tight regulation of the HBP in response to different cellular signals.
Assuntos
Proteína Quinase CDC2/genética , Proteínas de Ciclo Celular/genética , Quinases Ciclina-Dependentes/genética , Proteínas F-Box/genética , Mitose/genética , Proteínas de Saccharomyces cerevisiae/genética , Ubiquitina-Proteína Ligases/genética , Vias Biossintéticas/genética , Ciclo Celular/genética , Glucosamina/análogos & derivados , Glucosamina/genética , Glicosilação , Hexosaminas/genética , Fosforilação/genética , Saccharomyces cerevisiae/genética , Transdução de Sinais/genéticaRESUMO
The S. cerevisiae ISR1 gene encodes a putative kinase with no ascribed function. Here, we show that Isr1 acts as a negative regulator of the highly-conserved hexosamine biosynthesis pathway (HBP), which converts glucose into uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the carbohydrate precursor to protein glycosylation, GPI-anchor formation, and chitin biosynthesis. Overexpression of ISR1 is lethal and, at lower levels, causes sensitivity to tunicamycin and resistance to calcofluor white, implying impaired protein glycosylation and reduced chitin deposition. Gfa1 is the first enzyme in the HBP and is conserved from bacteria and yeast to humans. The lethality caused by ISR1 overexpression is rescued by co-overexpression of GFA1 or exogenous glucosamine, which bypasses GFA1's essential function. Gfa1 is phosphorylated in an Isr1-dependent fashion and mutation of Isr1-dependent sites ameliorates the lethality associated with ISR1 overexpression. Isr1 contains a phosphodegron that is phosphorylated by Pho85 and subsequently ubiquitinated by the SCF-Cdc4 complex, largely confining Isr1 protein levels to the time of bud emergence. Mutation of this phosphodegron stabilizes Isr1 and recapitulates the overexpression phenotypes. As Pho85 is a cell cycle and nutrient responsive kinase, this tight regulation of Isr1 may serve to dynamically regulate flux through the HBP and modulate how the cell's energy resources are converted into structural carbohydrates in response to changing cellular needs.
