Collagen matrix assembly is driven by the interaction of von Hippel-Lindau tumor suppressor protein with hydroxylated collagen IV alpha 2.
Oncogene
; 27(7): 1004-12, 2008 Feb 07.
Article
en En
| MEDLINE
| ID: mdl-17700531
ABSTRACT
Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene predisposes to vascular tumor formation in several organs. VHL regulates two evolutionary conserved pathways the targeting of hydroxylated hypoxia-inducible factor-alpha (HIF-alpha) for proteasomal degradation and the remodeling of extracellular matrix (ECM). The biochemical mechanisms of the ECM assembly pathway remain poorly defined. Here, we provide evidence supporting a biochemical role for VHL in ECM assembly. We show that VHL directly binds to the collagen IV alpha 2 (COL4A2) chain and that this interaction is necessary for its assembly into the ECM. The VHL-COL4A2 interaction is dependent on endoplasmic reticulum (ER)-mediated COL4A2 hydroxylation and independent of cytosolic, hypoxia regulated HIF-alpha-modifying enzymes. We find that the N-terminal tail of COL4A2 protrudes from the ER lumen into the cytosol where it is bound by VHL. Failure of VHL to interact with COL4A2 correlates with loss of collagen IV network formation in vitro and collagen IV remodeling in vivo. Our data suggest a HIF-alpha-independent role for the VHL-COL4A2 interaction in suppression of angiogenic tumor formation through collagen IV network assembly.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Carcinoma de Células Renales
/
Colágeno Tipo IV
/
Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau
/
Matriz Extracelular
Límite:
Humans
Idioma:
En
Revista:
Oncogene
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Año:
2008
Tipo del documento:
Article
País de afiliación:
Canadá