Regulation of the G1 to S transition by the ubiquitin pathway

Abstract

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. ß

The von Hippel–Lindau tumor suppressor gene product represses oncogenic β-catenin signaling in renal carcinoma cells

“…E-cadherin pull-down studies demonstrated increased cytoplasmic ␤-catenin in HGFstimulated VHL-negative RCC cells and blockade of this event upon ectopic VHL expression. ␤-Catenin is known to interact with the F-box proteins ␤-TrCP or Ebi in E3 ligase complexes; nevertheless, pVHL could be a component of an E3 complex that targets ␤-catenin for polyubiquitination in renal epithelial cells (44,45). Hybrid E3 ubiquitin ligases comprised of both SCF (Skp1͞Cul1͞F-box) and VBC (VHL͞EloB͞EloC)-Cul2 components have been shown to regulate ␤-catenin degradation in other cell types (46).…”

Deregulated degradation of the cdk inhibitor p27 and malignant transformation

“…SCF complexes represent an evolutionarily conserved class of E3 enzymes containing four subunits: Skp1, Cul1, one of many F-box proteins and Roc1/Rbx1 (reviewed in [24]). Antisense oligonucleotides to Skp2 or overexpression of a dominant negative Skp2 mutant stabilizes p27 in vivo [21].…”

DUB-3, a Cytokine-inducible Deubiquitinating Enzyme That Blocks Proliferation

“…Another large group of proteins involved in this process are the deubiquitinating enzymes, a family of ubiquitin-specific proteases that cleave ubiquitin from ubiquitinconjugated proteins and are thought to act at several points in the ubiquitin pathway, including polyubiquitin precursor processing, the removal of ubiquitin from substrates to rescue them from degradation, and the removal of residual ubiquitin to aid proteasomal degradation (7). These enzymes are classified into two main sub-families, the ubiquitin processing proteases (UBPs) 1 and the ubiquitin carboxyl-terminal hydrolases (UCHs), which are both cysteine proteases whose active sites contain a cysteine, histidine, and aspartate residue (8). The UBPs vary greatly in size and structural complexity, but all UBPs contain six conserved homology domains (DHI-DHVI).…”