Featured Grad Paper: Kristin Ambacher

Kristin Ambacher

The JNK- and AKT/GSK3β- Signaling Pathways Converge to Regulate Puma Induction and Neuronal Apoptosis Induced by Trophic Factor Deprivation.


Ambacher KK
, Pitzul KB, Karajgikar M, Hamilton A, Ferguson SS, Cregan SP.
PLoS One. 2012; 7(10): e46885.

Summary of paper in Kristin's words:

"Apoptosis is a form of programmed cell death that is involved in many natural processes including embryonic development, response to pathogens and cell turnover.  However, aberrant apoptosis has been implicated in several disease including neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease.  Therefore determining the way cells in the brain undergo this process is key to developing therapies and treatments for these diseases.  Apoptosis is controlled by a group of proteins called the Bcl-2 family proteins and one in particular, called Bax, is known to be critical for execution of this process.  How Bax activation is controlled during cell death remains to be determined, however several kinase pathways, namely the AKT, GSK3 and JNK family, have been implicated in this event. Our study sought to determine the mechanism by which AKT, GSK3 and JNK control Bax activation and subsequent apoptosis in neurons.  We initiated apoptotic signaling in cerebellar granule primary neuronal cultures by withdrawing potassium from their growth medium; this is a well established model of Bax-dependent apoptosis and has also been shown to involve AKT, GSK3 and JNK signaling.  We found that following potassium withdrawal a pro-apoptotic Bcl2 family member, Puma, was highly upregulated and that Puma is required for apoptosis both in these cultured cells as well as in the mouse developing cerebellum as cells and mice lacking Puma showed significantly less apoptosis.  Furthermore, we demonstrated that Puma upregulation was dependent on JNK activation and AKT inactivation and that AKT inactivation induces Puma through a GSK3-dependent mechanism.  Finally, we have shown that the JNK pathway and the AKT/GSK3 pathway converge to regulate FOXO3a, a transcription factor, which then in turn leads to upregulation of Puma.  In summary, we have identified a novel link between the JNK and AKT/GSK3 kinase pathways and the regulation of Bax activation, through regulating Puma induction.   We suggest that this pro-apoptotic protein, Puma, may be critical in the regulation of neuronal apoptosis in neurodegenerative diseases."

Kristin's Bio:

Kristin AmbacherI was born here in London, and grew up here in the north end of the city.  I decided to go to Western for university because I knew they had a great science program and because I was affiliated with the varsity volleyball program here.  I did my undergrad in the Department of Biology, mainly focusing my courses in the Genetics module.  During my undergrad I worked in an Evolution and Ecology lab under Dr. Bryan Neff which gave me the opportunity to travel to Trinidad to collect samples and to spend some time at the Queen’s University Biology Station (QUBS) near Kingston, Ontario.  I also got a taste for molecular work, working in the Molecular studies in Biodiversity, Ecology and Environmental Sciences (MoBEES).   After finishing my degree in Biology and a fourth year thesis project focused on ecology I decided I was interested in switching into research that was more health related, so I started a graduate degree in Physiology with Dr. Sean Cregan.  My project focuses on the signaling pathways and mechanisms that control Puma upregulation during neuronal cell death.  We’re interested in determining which transcriptional activation mechanisms link upstream kinase signaling with Puma mRNA induction because Puma has become established as a critical protein in neuronal apoptosis.

Outside the lab I like to stay active, playing volleyball and soccer and dancing salsa.  I also am trying to learn German because my dad’s family is from Germany and I’ve always wanted to be able to speak to them in German.  In January I will take over as one of the coordinators for the Let’s Talk Science program here at Western and I’ve been involved as a volunteer with the program for the past three years. It’s a great program and it’s a great way to remind yourself how much fun science can be! After my PhD my goal is move over to Europe and live there for a few years, maybe teaching at a university or doing a post-doc in a lab overseas.  I love to travel and Europe is my favorite destination – I can’t wait!

Innovation and Excellence in Research and Teaching