Ubiquitin

2000 Lasker Award to Ciechanover, Hershko and Varshavsky

Regulation of Protein Degradation: Ubiquitin-Dependent Proteolysis.

"Before closing, let me tell you how important ubiquitination has turned out to be. Ubiquitination-triggered protein degradation is at the very core of biology. It influences not only normal cell division, but also the disordered cell division and differentiation that leads to cancer. Ubiquitination is responsible for the inflammatory process that leads acutely to fever, shock and death - and chronically to arthritis and other degenerative diseases. Several human genetic diseases result from defects in ubiquitination. I estimate that 1 out of 10 papers in current biology journals deals with ubiquitination in one system or another." ......Nobel Prize Winner Michael S. Brown

Many regulatory proteins are rapidly degraded. In addition, the classic response to starvation, nutrient deprivation and/or stress includes an increased rate of intracellular proteolysis. Ubiquitin has been shown to be involved in the regulated proteolysis of damaged proteins, as well as short-lived regulatory molecules such as cyclins, c-mos, p53, c-myc, c- fos, c-jun, and NF-kB. This system also has been shown to respond to glucocorticoids during fasting, to TNF as may occur in cachexia, to metabolic acidosis, to interferon gamma elicited by viral infection, to feeding cycles, to heat-shock, and to protein damage. Cellular proteolysis is regulated in response to intracellular signals, many of which are ill-defined. Both the lysosomal and the ubiquitin-dependent systems function as compartmentalized multienzyme systems which sequester proteolytic sites from the bulk of soluble proteins. The lysosome packages its proteases in an acidic compartment and acquires substrates by either autophagy or selective uptake through the hsp73 receptor. The ubiquitin-dependent system sequesters its proteolytic sites by inclusion in a multi-enzyme complex

and selects substrates by ubiquitination of the target protein. This post-translational covalent modification commits the target proteins to degradation. As such, the enzymes which reverse this modification (the UCH and UBP proteins) are also important in regulating flux through this system. Our current efforts concentrate on characterizing the structure, function and substrate specificity of the UCH/UBP families of enzymes. The long-term goals are to elucidate this system of regulation and describe how it functions in normal metabolism, in the stress response, and in the control of cell- cycle events. The results will have broad implications for understanding oncogenes, carcinogenesis, receptor function, and pathological protein turnover such as inclusion body formation or cachexia.

For Further information, see

Protein Degradation Resource

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