Tracheal development and the von Hippel-Lindau tumor suppressor homolog in Drosophila.
von Hippel-Lindau disease is a hereditary cancer syndrome. Mutations in the VHL tumor suppressor gene predispose individuals to highly vascularized tumors. However, VHL-deficient mice die in utero due to a lack of vascularization in the placenta. To resolve the contradiction, we cloned the Drosophila VHL homologue (d-VHL) and studied its function. It showed an overall 50% similarity to the human counterpart and 76% similarity in the crucial functional domain: the elongin C binding site. The putative d-VHL protein can bind Drosophila elongin C in vitro. During embryogenesis, d-VHL is expressed in the developing tracheal regions where tube outgrowth no longer occurs. Reduced d-VHL activity (using RNA interference methodology) caused breakage of the main vasculature accompanied by excessive looping of smaller branches, whereas over-expression caused a general lack of vasculature. Importantly, human VHL can induce the same gain-of-function phenotypes. VHL is likely involved in halting cell migration at the end of vascular tube outgrowth. Loss of VHL activity can therefore lead to disruption of major vasculature (as in the mouse embryo), which requires precise cell movement and tube fusion, or ectopic outgrowth from existing secondary vascular branches (as in the adult tumors). Oncogene (2000) 19, 2803 - 2811
Adryan
B
B
Center for Molecular and Structural Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, SC 29425, USA.
Decker
H J
HJ
Papas
T S
TS
Hsu
T
T
D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D004330:Drosophila; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D008025:Ligases; D008969:Molecular Sequence Data; D010641:Phenotype; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D014132:Trachea / Q000196:embryology*; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D011506:Proteins; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human