The polyamines spermine, spermidine and their precursor putrescine are ubiquitous organic polycations that play an important role in regulating fundamental cellular processes, most notably the process of cell growth and proliferation. Depletion of cellular polyamines results in growth cessation, while increased intracellular polyamine levels are associated with cancer. Therefore, polyamines concentration must be maintained within a narrow optimal range. This is achieved by regulation at multiple control levels that include synthesis, uptake, excretion and inter-conversion.
Our laboratory is investigating the mechanisms that control the intracellular levels of polyamines and the role polyamines play in regulating fundamental cellular processes.
Much of our study focuses on Ornithine Decarboxylase (ODC), the first and rate- limiting enzyme in the polyamine biosynthesis pathway. ODC activity and the level of the resulting polyamines are stimulated by various trophic stimuli and oscillate along the cell cycle. A key element enabling rapid modulation of ODC activity is its extremely short intracellular half-life. Interestingly, ODC degradation is executed by the action of the 26S proteasome, without requiring its ubiquitination!
Instead, ODC is targeted to degradation by a polyamine-induced protein termed Antizyme (Az), whose synthesis requires a unique process of programmed ribosomal frameshifting that is stimulated by polyamines. Thus, Az, whose production serves as a sensor for the intracellular polyamine concentration, functions as a key element of an autoregulatory circuit that regulates polyamine levels.
Another arm of ODC regulation involves its homolog, termed antizyme-inhibitor (AzI), which regulates ODC degradation by competing with ODC for binding to Az. However, as opposed to ODC, AzI whose degradation is ubiquitin-dependent, is stabilized by the interaction with Az.
We are investigating the degradation mechanisms of ODC and its regulators, and study the interplay between these proteins. Additionally, identification of the proteasomal components that mediate the ubiquitin-independent recognition of the Az-ODC complex is in the center of our interests.
A major goal of our studies is to understand the mechanisms that underline the need for polyamines in the process of mammalian cell proliferation. This is achieved by monitoring the effect of polyamine depletion and re-addition on transcriptional and translational processes by gene expression profiling, polysomal fractionations and other biochemical and genetic methods.
We also exploit our ability to manipulate cellular polyamines to control cellular growth processes and for the development of new therapeutic approaches to control hyper-proliferative diseases.