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Genetic deletion of the long isoform of the von Hippel-Lindau tumour suppressor gene product alters microtubule dynamics


Frew, Ian J; Smole, Zlatko; Thoma, Claudio R; Krek, Wilhelm (2013). Genetic deletion of the long isoform of the von Hippel-Lindau tumour suppressor gene product alters microtubule dynamics. European Journal of Cancer, 49(10):2433-2440.

Abstract

The von Hippel-Lindau tumour suppressor protein (pVHL) controls distinct cellular responses ranging from targeting hypoxia inducible factor α (HIFα) subunits for degradation and promotion of chromosomal stability to the regulation of microtubule dynamics. pVHL is produced in mammalian cells as a long and a short isoform, derived from alternate translational initiation sites in a single Vhl mRNA. However, it is unclear whether these isoforms have different cell biological activities that may represent different tumour suppressor activities of pVHL. Through a knock-in strategy to mutate the first translational initiation site from methionine to leucine (M1L) we have genetically deleted the pVHL long protein isoform in mice, allowing dissection of isoform-specific functions of pVHL. Vhl(M1L/M1L) mice exhibit no obvious phenotypic abnormalities. While numerous pVHL-mediated activities, including degradation of HIFα transcription factors, are unaffected, microtubule dynamics are altered in primary cells derived from Vhl(M1L/M1L) mice to an extent similar to that seen following complete loss of pVHL function. We conclude that the microtubule-regulating function and the HIFα-regulating function of pVHL are separable activities mediated by different protein isoforms.

Abstract

The von Hippel-Lindau tumour suppressor protein (pVHL) controls distinct cellular responses ranging from targeting hypoxia inducible factor α (HIFα) subunits for degradation and promotion of chromosomal stability to the regulation of microtubule dynamics. pVHL is produced in mammalian cells as a long and a short isoform, derived from alternate translational initiation sites in a single Vhl mRNA. However, it is unclear whether these isoforms have different cell biological activities that may represent different tumour suppressor activities of pVHL. Through a knock-in strategy to mutate the first translational initiation site from methionine to leucine (M1L) we have genetically deleted the pVHL long protein isoform in mice, allowing dissection of isoform-specific functions of pVHL. Vhl(M1L/M1L) mice exhibit no obvious phenotypic abnormalities. While numerous pVHL-mediated activities, including degradation of HIFα transcription factors, are unaffected, microtubule dynamics are altered in primary cells derived from Vhl(M1L/M1L) mice to an extent similar to that seen following complete loss of pVHL function. We conclude that the microtubule-regulating function and the HIFα-regulating function of pVHL are separable activities mediated by different protein isoforms.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2013
Deposited On:12 Apr 2013 07:17
Last Modified:07 Dec 2017 20:57
Publisher:Elsevier
ISSN:0959-8049
Publisher DOI:https://doi.org/10.1016/j.ejca.2013.02.024
PubMed ID:23541568

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