The interaction of the von Hippel-Lindau tumor suppressor and heterochromatin protein 1

Abstract

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor is associated with renal carcinoma, hemangioblastoma and pheochromocytoma. The VHL protein is a component of a ubiquitin ligase complex that ubiquitinates and degrades hypoxia inducible factor-α (HIF-α). Degradation of HIF-α by VHL is proposed to suppress tumorigenesis and tumor angiogenesis. Several lines of evidence also suggest important roles for HIF-independent VHL functions in tumor suppression and other biological processes. Using GST-VHL pull-down experiment and mass spectrometry, we detected an interaction between VHL and heterochromatin protein 1 (HP1). We identified a conserved HP1-binding motif (PXVXL) in the β domain of VHL, which is disrupted in a renal carcinoma-associated P81S mutant. We show that the VHL P81S mutant displays reduced binding to HP1, yet retains the ability to interact with elongin B, elongin C, and cullin 2 and is fully capable of degrading HIF-α. We also demonstrate that HP1 increases the chromatin association of VHL. These results suggest a role for the VHL-HP1 interaction in VHL chromatin targeting.

Consequences of VHL Loss on Global DNA Methylome

“…Although the precise mechanism(s) by which VHL regulates the epigenome remains an outstanding question, it is conceivable that VHL itself directly influences chromatin organisation. In support of such notion, VHL was observed to bind to heterochromatin associated protein HP1 29 . Interestingly, this interaction was not related to the degradation function of VHL instead speculating that HP1 recruits VHL to chromatin.…”

The structure and regulation of Cullin 2 based E3 ubiquitin ligases and their biological functions

“…VHL limited EGFR signaling by promoting c-Cbl-independent poly-ubiquitination and lysosome-independent degradation of the activated EGFR [ 64 ]. In addition, some E3-ligase independent functions of VHL were reported [ 65 – 68 ]. In these cases, VHL interacted with other proteins, regulated their functions, but did not promote their poly-ubiquitination and degradation.…”

The role of SON in splicing, development, and disease

“…6 In leukemia cells, SON interacts with growth arrest inducing protein AML1-ETO instead of its tumorgenic isoform AML1-ETO(C663S). 33,54 In addition, SON translocates from nuclear speckles to the cytoplasm in t(8;21)+ leukemia cells. SON also interacts with tumor suppressor protein von Hippel-Lindau in 786-O renal carcinoma cells.…”

“…SON also interacts with tumor suppressor protein von Hippel-Lindau in 786-O renal carcinoma cells. 54 The expression of SON has been detected in various cancer cell lines such as leukemia-derived, HeLa, and pancreatic cancer cell lines. 16,21,29,30,33,34,55 SON deficiency inhibited the tumorigenicity of pancreatic tumor cells in vivo.…”