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Brain tumor |
REGULATION OF
POLYAMINE HOMEOSTASIS IN MAMMALIAN CELLS
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The Mitchell laboratory has been investigating polyamine homeostasis as a biochemical control system critical to growth and maintenance of healthy human tissues. Abnormalities in this particular system are associated with various diseased states including neurological dysfunction, Alzheimer's, and cancer. By elucidating the normal workings of this system we hope to lead the way to discovery of treatments and cures for these and other human ailments. |
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Although the polyamines are essential for normal cell physiology, we still do not know which of the many potential interactions of these organic cations are critical for cell function. Clearly, there are several known polyamine actions that suggest that the intracellular levels of these compounds serve as a very important control system. In support of this contention, there are several lines of evidence that directly link abnormalities in the regulation of polyamine levels with mammalian cancer. The understanding and control of cancerous growth will therefore require a more complete comprehension of the mechanisms involved in maintaining normal polyamine levels. |
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Some Functions:
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| Biosynthesis of the polyamines begins with the conversion of ornithine to putrescine by the enzyme ornithine decarboxylase (ODC). Putrescine is subsequently converted to spermidine and then spermine, through the actions of the enzymes S-adenosyl-L-metionine decarboxylase (SAMDC) and spermidine/spermine synthases. | |
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Once a cell achieves its normal level of polyamines then the biosynthetic pathway is down regulated to prevent over accumulation of these potentially toxic compounds. Once spermine or spermidine concentrations increase above a set level, they induce the synthesis of a regulatory protein called ODC-antizyme (Az). Antizyme both binds ODC to inactivate it and it stimulates a very rapid degradation of the ODC protein by the 26S proteasome. Thus increased levels of spermidine and spermine feedback regulate their biosynthetic pathway by inhibiting the initial reaction, the synthesis of putrescine. |
| Mammalian cells are also capable of acquiring polyamines from their environment by use of an aggressive polyamine transporter. Interestingly, over accumulation of polyamines by this route is also prevented by feedback inhibition. The activity of the polyamine transporter is reversibly inhibited by increases in antizyme. Thus antizyme emerges as a critical control for maintaining at least two of the most critical reactions in polyamine homeostasis. Therefore, we place a major emphasis on understanding the factors controlling antizyme synthesis and function. |
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This low abundance, regulatory protein exhibits several highly unusual characteristics. Its synthesis is controlled at the translational level by polyamines stimulating the induction of a +1 frameshift that is essential for complete translation of the message. Once synthesized, antizyme protein is processed to several slightly smaller, but still active, protein forms. Antizyme protein has a very high affinity for another protein, antizyme inhibitor (AIn), and this reaction prevents the ability of antizyme to stimulate the degradation of ODC. Finally, antizyme itself is a rather labile protein and steady-state levels of antizyme can be controlled by modifications in this half-life. As detailed elsewhere, projects of the students in this laboratory explore antizyme synthesis, activation, maturation, stability and its interaction with ODC, mitochondria and antizyme-inhibitor. Our goal is to use this understanding to design and test methods of preventing or limiting the abnormal growth of cancer. |
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For a more detailed description of the background information leading to our current studies click here. |
