Regulation of the G1 to S transition by the ubiquitin pathway.
This year the most prestigious prize in medical sciences, the Lasker Award, has been presented to the three scientists who discovered the ubiquitin pathway: Aaron Ciechanover, Avram Hershko, and Alexander Varshavsky [Nature Med. 6 (2000) 1073-1081]. During a time when the scientific community was focused on understanding how proteins were synthesized, they intently pursued the novel idea that cells were programmed to selectively destroy proteins. Their work led to the identification of an elaborate system of protein degradation targeting a myriad of cellular substrates. A small protein called ubiquitin is at the center of this process. Although the ubiquitin pathway was first described in the early 1980s, it has only more recently advanced to the forefront of basic research as a significant regulatory network within the cell. The field continues to grow as new ubiquitination enzymes and novel functions of this system are identified. Scientists are focused on elucidating the mechanisms by which cells deploy the ubiquitin pathway to control levels of selected proteins, such as cell cycle regulatory proteins, transcription factors and signaling molecules. Accelerated or decelerated rates of degradation of particular substrates participate in the genesis of many human diseases. Thus, understanding the mechanisms that confer specificity to the ubiquitin system will allow the development of novel therapeutic approaches to target aberrations in this pathway underlying tumorigenesis and other human pathologies.
DeSalle
L M
LM
Department of Pathology and Kaplan Comprehensive Cancer Center, MSB 548, New York University Medical Center, 550 First Avenue, New York, NY 10016, USA.
Pagano
M
M
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D016193:G1 Phase; D006801:Humans; D008025:Ligases / Q000737:chemistry / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D010453:Peptide Synthases / Q000737:chemistry / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D021122:Protein Subunits; D016196:S Phase; D044843:SKP Cullin F-Box Protein Ligases; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism*
C080443:CDC4 protein, S cerevisiae; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D009097:Multienzyme Complexes; D021122:Protein Subunits; D029701:Saccharomyces cerevisiae Proteins; D014452:Ubiquitins; C046288:ubiquitin carrier proteins; D044763:Ubiquitin-Conjugating Enzymes; D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008025:Ligases; D010453:Peptide Synthases