The von Hippel-Lindau Tumor Suppressor Protein Promotes c-Cbl-Independent Poly-Ubiquitylation and Degradation of the Activated EGFR

Somatic mutations or reduced expression of the von Hippel-Lindau (VHL) tumor suppressor occurs in the majority of the clear cell renal cell carcinoma (ccRCC) and is a causal factor for the pathogenesis of ccRCC. pVHL was reported to suppress the oncogenic activity of Epidermal Growth Factor Receptor (EGFR) by reducing the expression of the EGFR agonist TGF-α and by reducing the translation efficiency of EGFR itself. Furthermore, it was reported that pVHL down-regulates activated EGFR by promoting efficient lysosomal degradation of the receptor. These modes of negative regulation of EGFR by pVHL were dependent on Hypoxia Inducible Factor (HIF). In this study, we report that HIF was not the only factor stabilizing the activated EGFR in VHL-deficient ccRCC cells. Down-regulation of endogenous HIF in these cells had little effect on the turnover rates of the activated EGFR. Furthermore, neither pretreatment with lysomomal inhibitors pretreatment nor down-regulation of c-Cbl, a major E3 ubiquitin ligase that targets the activated EGFR for lysosomal degradation, significantly increased the stabilities of EGFR in VHL-expressing ccRCC cells. In contrast, pretreatment with proteasomal inhibitors extended EGFR lifetime and led to similar EGFR half-lives in VHL-expressing and VHL-deficient ccRCC cells. Down-regulation of c-Cbl in VHL-deficient ccRCC cells revealed that the c-Cbl and pVHL collaborated to down-regulate the activated EGFR. Finally, we found that pVHL promoted the poly-ubiquitylation of the activated EGFR, and this function was c-Cbl-independent. Thus these results indicate that pVHL limits EGFR signaling by promoting c-Cbl-independent poly-ubiquitylation of the activated receptor, which likely results in its degradation by proteasome

The role of the ubiquitination–proteasome pathway in breast cancer: Ubiquitin mediated degradation of growth factor receptors in the pathogenesis and treatment of cancer

Aberrant activity of growth factor receptors has been implicated in the pathogenesis of a wide variety of malignancies. The negative regulation of signaling by growth factor receptors is mediated in large part by the ubiquitination, internalization, and degradation of the activated receptor. Over the past few years, considerable insight into the mechanisms that control receptor downregulation has been gained. There are also data suggesting that mutations that lead to inhibition of downregulation of growth factor receptors could play a role in the pathogenesis of cancer. Therapies directed at enhancing the degradation of growth factor receptors offer a promising approach to the treatment of malignancies

Employment protection regulations in local public transport: how do they affect production efficiency and competition?

Employment protection in local public transport raises crucial questions in a period of changing regimes of how transport services are purchased by the government. Traditionally the government either produced passenger services itself or negotiated with private businesses. However, competitive tendering is increasingly introduced in European countries. This occasions much debate, as many – especially labour unions – argue that competitive tendering worsens working conditions. They are of the opinion that employees pay for the increased production efficiency gained through competitive tendering, as “slack” is reduced and employment relations become unstable. On this background there is a debate going on in Norway on how to regulate employment protection in the event of competitive tendering processes in local public transport. One alternative is to give the workers the same rights when competitive tendering is carried out, as they would have had in the events of transfer of an undertaking. This is practised in the capital areas of Denmark and Sweden and introduced in one Norwegian region. In a report by the Institute of Transport Economics (Osland/Leiren 2006), we map the expected results of franchising on employment relations which refer to employment protection, wages and pensions, working time, qualification requirements, and workers’ participation. We conclude that franchising is most crucial to employment protection. We suggest alternative ways of limiting this effect. One of the alternatives is to adopt employees’ rights in the events of transfer of an undertaking. However, the effects of such a regulation may vary according to different factors such as whether the employees have already been through a process of competitive tendering. We propose to map such factors and discuss the extent of how the regulation may affect employment relations. Moreover, we ask the question: How will the regulation affect other areas such as competition, production costs and administrative costs? Does the regulation cause unwanted risks for the Public Transport Administration and bus companies, thereby rising costs and distortion of competition