Presentation description

Polyamines are small, positively charged molecules essential for cell proliferation, nucleic acid stabilization, and overall cellular homeostasis. Their levels are tightly regulated, and dysregulation is a hallmark of many cancers. Understanding how polyamine biosynthesis is controlled is critical to uncovering new therapeutic targets. Adenosylmethionine decarboxylase 1 (AMD1) is a rate-limiting enzyme in this pathway responsible for producing spermidine and spermine. Despite its importance, little is known about how AMD1 is regulated at the transcriptional or post-translational level.

Our research aims to uncover the molecular mechanisms controlling AMD1 abundance. Using HEK293 cells, we combined pharmacological perturbation, transcript and protein analysis, and genetic manipulation to assess AMD1 regulation under polyamine-depleted and polyamine-overloaded conditions. Quantitative proteomics revealed that inhibiting the ubiquitin-proteasome system increases AMD1 protein levels, suggesting post-translational regulation. Transcript-level responses also suggest an additional layer of RNA-level control, indicating AMD1 expression may be shaped by multiple pathways. These findings support the existence of upstream regulators that respond to changes in polyamine levels to control AMD1 stability.

To build on these findings, we are using genetic and biochemical approaches to investigate candidate ubiquitin ligases and other regulatory proteins that may modulate AMD1 abundance. Understanding how AMD1 is controlled under different metabolic conditions will provide deeper insight into how cells fine-tune polyamine biosynthesis.