Biology subjects

Israelsen, W. J.

Publications and source records attributed to Israelsen, W. J..

3 recordsLinked to original sources

bioRxiv2021

Pyruvate kinase M1 suppresses development and progression of prostate adenocarcinoma

Most cancers, including prostate cancers, express the M2 splice isoform of pyruvate kinase (Pkm2). This isoform can promote anabolic metabolism to support cell proliferation; however, Pkm2 expression is dispensable for many cancers in vivo. Pyruvate kinase M1 (Pkm1) isoform expression is restricted to relatively few tissues and has been reported to promote growth of select tumors, but the role of PKM1 in cancer has been less studied. Pkm1 is expressed in normal prostate tissue; thus, to test how differential pyruvate kinase isoform expression affects cancer initiation and progression we generated mice harboring a conditional allele of Pkm1 and crossed this allele, as well as a Pkm2 conditional allele, to a Pten loss-driven prostate cancer model. We found that Pkm1 loss leads to Pkm2 expression and accelerates prostate cancer, while deletion of Pkm2 leads to increased Pkm1 expression and suppresses cancer. Consistent with these data, a small molecule pyruvate kinase activator that mimics a PKM1-like state suppresses progression of established prostate tumors. PKM2 expression is retained in most human prostate cancers, arguing that pharmacological PKM2 activation may be beneficial for some prostate cancer patients.

cancer biology↗

bioRxiv2020

The meadow jumping mouse genome and transcriptome suggest mechanisms of hibernation

Hibernating mammals exhibit medically relevant phenotypes, but the genetic basis of hibernation remains poorly understood. Using the meadow jumping mouse (Zapus hudsonius), we investigated the genetic underpinnings of hibernation by uniting experimental and comparative genomic approaches. We assembled a Z. hudsonius genome and identified widespread expression changes during hibernation in genes important for circadian rhythm, membrane fluidity, and cell cycle arrest. Tissue-specific gene expression changes during torpor encompassed Wnt signaling in the brain and structural and transport functions in the kidney brush border. Using genomes from the closely related Zapus oregonus (previously classified as Z. princeps) and leveraging a panel of hibernating and non-hibernating rodents, we found selective pressure on genes involved in feeding behavior, metabolism, and cell biological processes potentially important for function at low body temperature. Leptin stands out with elevated conservation in hibernating rodents, implying a role for this metabolic hormone in triggering fattening and hibernation. These findings illustrate that mammalian hibernation requires adaptation at all levels of organismal form and function and lay the groundwork for future study of hibernation phenotypes.

genomics↗

bioRxiv2020

Breeding and hibernation of captive meadow jumping mice (Zapus hudsonius)

Hibernating mammals exhibit unique metabolic and physiological phenotypes that have potential applications in medicine or spaceflight, yet our understanding of the genetic basis and molecular mechanisms of hibernation is limited. The meadow jumping mouse, a small North American hibernator, exhibits traits - including a short generation time - that would facilitate genetic approaches to hibernation research. Here we report the collection, captive breeding, and laboratory hibernation of meadow jumping mice. Captive breeders in our colony produced a statistically significant excess of male offspring and a large number of all-male and all-female litters. We confirmed that short photoperiod induced pre-hibernation fattening, and cold ambient temperature facilitated entry into hibernation. During pre-hibernation fattening, food consumption exhibited non-linear dependence on both body mass and temperature, such that food consumption was greatest in the heaviest animals at the coldest temperatures. Meadow jumping mice exhibited a strong circadian rhythm of nightly activity that was disrupted during the hibernation interval. We quantified the length and timing of torpor bouts and arousals obtained from an uninterrupted recording of a hibernating female. Over a 90.6 day hibernation interval, torpor bouts ranged from 2.1 to 12.8 days (mean 7.7 days), and arousal length was relatively constant with a mean length of 9.6 hours. We conclude that it is possible to study hibernation phenotypes using captive-bred meadow jumping mice in a laboratory setting.

physiology↗