Human asparagine synthetase associates with the mitotic spindle.

Chalongrat Noree,Elena Monfort,Vorasuk Shotelersuk

doi:10.1242/bio.038307

Chalongrat Noree, Elena Monfort + Show 1 more

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https://doi.org/10.1242/bio.038307

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Abstract

ABSTRACTCancer cells are characterized by extensive reprogramming of metabolic pathways in order to promote cell division and survival. However, the growth promotion effects of metabolic reprogramming can be due to moonlighting functions of metabolic enzymes as well as the redirection of flux through particular pathways. To identify metabolic enzymes that might have potential moonlighting functions in oncogenesis, we have examined recent screens of the yeast GFP strain collection for metabolic enzymes that have been implicated in cancer metabolism with an unusual subcellular localization. Asparagine synthetase forms filaments in yeast in response to nutrient limitation and is part of a pathway that is a chemotherapy target in acute lymphoblastic leukemia. Interestingly, while yeast asparagine synthetase forms cytoplasmic filaments in response to nutrient stress, human asparagine synthetase is associated with the centrosomes and mitotic spindles. This localization is disrupted by both nocodazole and asparaginase treatments. This failure to localize occurs even though asparagine synthetase is highly upregulated in response to asparaginase treatment. Together, these results argue that human asparagine synthetase undergoes regulated recruitment to the mitotic spindles and that it may have acquired a second role in mitosis similar to other metabolic enzymes that contribute to metabolic reprogramming in cancer cells.

Highlights

Since the discovery of the Warburg effect in the 1920s, alterations in metabolic activity have long been associated with oncogenesis and tumor progression
Single gene deletion analysis suggests that Asn1p is a major contributor to yeast asparagine synthetase assembly and that Asn2p cannot assemble without Asn1p (Fig. 1B)
While yeast asparagine synthetase forms cytoplasmic filaments that are separate from the mitotic spindle, human asparagine synthetase is recruited to both centrosomes and spindle microtubules

Summary

Introduction

Since the discovery of the Warburg effect in the 1920s, alterations in metabolic activity have long been associated with oncogenesis and tumor progression. The last decade has seen an explosion of insights into how these metabolic changes are linked to the rapid growth and development of tumors (DeBerardinis et al, 2008; Hanahan and Weinberg, 2011; Menendez and Alarcón, 2014; Ward and Thompson, 2012). While most of these studies have focused on how various metabolic pathways are optimized to facilitate cell growth and division, recent work has shown that these changes to metabolic enzymes might drive oncogenesis due to nonmetabolic moonlighting functions of the enzyme. PKM2 can regulate transcription as either a transcriptional co-activator for HIF-1 or as a protein kinase that targets transcription factors, such as STAT3 (Demaria and Poli, 2012)

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