Hypoxia Inducible Factor Activates the Transforming Growth Factor-α/Epidermal Growth Factor Receptor Growth Stimulatory Pathway in VHL-/- Renal Cell Carcinoma Cells

Lakshman Gunaratnam, Melissa Morley, Aleksandra Franovic, Natalie De Paulsen, Karim Mekhail, Doris A E Parolin, Eijiro Nakamura, Ian A J Lorimer, Stephen Lee

Research output: Contribution to journalArticle

160 Citations (Scopus)

Abstract

Bi-allelic-inactivating mutations of the VHL tumor suppressor gene are found in the majority of clear cell renal cell carcinomas (VHL-/- RCC). VHL-/- RCC cells overproduce hypoxia-inducible genes as a consequence of constitutive, oxygen-independent activation of hypoxia inducible factor (HIF). While HIF activation explains the highly vascularized nature of VHL loss lesions, the relative role of HIF in oncogenesis and loss of growth control remains unknown. Here, we report that HIF plays a central role in promoting unregulated growth of VHL-/- RCC cells by activating the transforming growth factor-α (TGF-α)/epidermal growth factor receptor (EGF-R) pathway. Dominant-negative HIF and enzymatic inhibition of EGF-R were equally efficient at abolishing EGF-R activation and serum-independent growth of VHL-/- RCC cells. TGF-α is the only known EGF-R ligand that has a VHL-dependent expression profile and its overexpression by VHL-/- RCC cells is a direct consequence of HIF activation. In contrast to TGF-α, other HIF targets, including vascular endothelial growth factor (VEGF), were unable to stimulate serum-independent growth of VHL-/- RCC cells. VHL-/- RCC cells expressing reintroduced type 2C mutants of VHL, and which retain the ability to degrade HIF, fail to overproduce TGF-α and proliferate in serum-free media. These data link HIF with the overproduction of a bona fide renal cell mitogen leading to activation of a pathway involved in growth of renal cancer cells. Moreover, our results suggest that HIF might be involved in oncogenesis to a much higher extent than previously appreciated.

Original languageEnglish (US)
Pages (from-to)44966-44974
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number45
DOIs
StatePublished - Nov 7 2003
Externally publishedYes

Fingerprint

Transforming Growth Factors
Renal Cell Carcinoma
Epidermal Growth Factor Receptor
Chemical activation
Cells
Growth
Genes
Serum-Free Culture Media
Mitogens
Vascular Endothelial Growth Factor A
Tumors
Carcinogenesis
Hypoxia
Oxygen
Ligands
Cell Hypoxia
Tumor Suppressor Genes
Serum
Kidney
Mutation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Hypoxia Inducible Factor Activates the Transforming Growth Factor-α/Epidermal Growth Factor Receptor Growth Stimulatory Pathway in VHL-/- Renal Cell Carcinoma Cells. / Gunaratnam, Lakshman; Morley, Melissa; Franovic, Aleksandra; De Paulsen, Natalie; Mekhail, Karim; Parolin, Doris A E; Nakamura, Eijiro; Lorimer, Ian A J; Lee, Stephen.

In: Journal of Biological Chemistry, Vol. 278, No. 45, 07.11.2003, p. 44966-44974.

Research output: Contribution to journalArticle

Gunaratnam, Lakshman ; Morley, Melissa ; Franovic, Aleksandra ; De Paulsen, Natalie ; Mekhail, Karim ; Parolin, Doris A E ; Nakamura, Eijiro ; Lorimer, Ian A J ; Lee, Stephen. / Hypoxia Inducible Factor Activates the Transforming Growth Factor-α/Epidermal Growth Factor Receptor Growth Stimulatory Pathway in VHL-/- Renal Cell Carcinoma Cells. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 45. pp. 44966-44974.
@article{89e17e77027f4ff4ac614a669a81754c,
title = "Hypoxia Inducible Factor Activates the Transforming Growth Factor-α/Epidermal Growth Factor Receptor Growth Stimulatory Pathway in VHL-/- Renal Cell Carcinoma Cells",
abstract = "Bi-allelic-inactivating mutations of the VHL tumor suppressor gene are found in the majority of clear cell renal cell carcinomas (VHL-/- RCC). VHL-/- RCC cells overproduce hypoxia-inducible genes as a consequence of constitutive, oxygen-independent activation of hypoxia inducible factor (HIF). While HIF activation explains the highly vascularized nature of VHL loss lesions, the relative role of HIF in oncogenesis and loss of growth control remains unknown. Here, we report that HIF plays a central role in promoting unregulated growth of VHL-/- RCC cells by activating the transforming growth factor-α (TGF-α)/epidermal growth factor receptor (EGF-R) pathway. Dominant-negative HIF and enzymatic inhibition of EGF-R were equally efficient at abolishing EGF-R activation and serum-independent growth of VHL-/- RCC cells. TGF-α is the only known EGF-R ligand that has a VHL-dependent expression profile and its overexpression by VHL-/- RCC cells is a direct consequence of HIF activation. In contrast to TGF-α, other HIF targets, including vascular endothelial growth factor (VEGF), were unable to stimulate serum-independent growth of VHL-/- RCC cells. VHL-/- RCC cells expressing reintroduced type 2C mutants of VHL, and which retain the ability to degrade HIF, fail to overproduce TGF-α and proliferate in serum-free media. These data link HIF with the overproduction of a bona fide renal cell mitogen leading to activation of a pathway involved in growth of renal cancer cells. Moreover, our results suggest that HIF might be involved in oncogenesis to a much higher extent than previously appreciated.",
author = "Lakshman Gunaratnam and Melissa Morley and Aleksandra Franovic and {De Paulsen}, Natalie and Karim Mekhail and Parolin, {Doris A E} and Eijiro Nakamura and Lorimer, {Ian A J} and Stephen Lee",
year = "2003",
month = "11",
day = "7",
doi = "10.1074/jbc.M305502200",
language = "English (US)",
volume = "278",
pages = "44966--44974",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "45",

}

TY - JOUR

T1 - Hypoxia Inducible Factor Activates the Transforming Growth Factor-α/Epidermal Growth Factor Receptor Growth Stimulatory Pathway in VHL-/- Renal Cell Carcinoma Cells

AU - Gunaratnam, Lakshman

AU - Morley, Melissa

AU - Franovic, Aleksandra

AU - De Paulsen, Natalie

AU - Mekhail, Karim

AU - Parolin, Doris A E

AU - Nakamura, Eijiro

AU - Lorimer, Ian A J

AU - Lee, Stephen

PY - 2003/11/7

Y1 - 2003/11/7

N2 - Bi-allelic-inactivating mutations of the VHL tumor suppressor gene are found in the majority of clear cell renal cell carcinomas (VHL-/- RCC). VHL-/- RCC cells overproduce hypoxia-inducible genes as a consequence of constitutive, oxygen-independent activation of hypoxia inducible factor (HIF). While HIF activation explains the highly vascularized nature of VHL loss lesions, the relative role of HIF in oncogenesis and loss of growth control remains unknown. Here, we report that HIF plays a central role in promoting unregulated growth of VHL-/- RCC cells by activating the transforming growth factor-α (TGF-α)/epidermal growth factor receptor (EGF-R) pathway. Dominant-negative HIF and enzymatic inhibition of EGF-R were equally efficient at abolishing EGF-R activation and serum-independent growth of VHL-/- RCC cells. TGF-α is the only known EGF-R ligand that has a VHL-dependent expression profile and its overexpression by VHL-/- RCC cells is a direct consequence of HIF activation. In contrast to TGF-α, other HIF targets, including vascular endothelial growth factor (VEGF), were unable to stimulate serum-independent growth of VHL-/- RCC cells. VHL-/- RCC cells expressing reintroduced type 2C mutants of VHL, and which retain the ability to degrade HIF, fail to overproduce TGF-α and proliferate in serum-free media. These data link HIF with the overproduction of a bona fide renal cell mitogen leading to activation of a pathway involved in growth of renal cancer cells. Moreover, our results suggest that HIF might be involved in oncogenesis to a much higher extent than previously appreciated.

AB - Bi-allelic-inactivating mutations of the VHL tumor suppressor gene are found in the majority of clear cell renal cell carcinomas (VHL-/- RCC). VHL-/- RCC cells overproduce hypoxia-inducible genes as a consequence of constitutive, oxygen-independent activation of hypoxia inducible factor (HIF). While HIF activation explains the highly vascularized nature of VHL loss lesions, the relative role of HIF in oncogenesis and loss of growth control remains unknown. Here, we report that HIF plays a central role in promoting unregulated growth of VHL-/- RCC cells by activating the transforming growth factor-α (TGF-α)/epidermal growth factor receptor (EGF-R) pathway. Dominant-negative HIF and enzymatic inhibition of EGF-R were equally efficient at abolishing EGF-R activation and serum-independent growth of VHL-/- RCC cells. TGF-α is the only known EGF-R ligand that has a VHL-dependent expression profile and its overexpression by VHL-/- RCC cells is a direct consequence of HIF activation. In contrast to TGF-α, other HIF targets, including vascular endothelial growth factor (VEGF), were unable to stimulate serum-independent growth of VHL-/- RCC cells. VHL-/- RCC cells expressing reintroduced type 2C mutants of VHL, and which retain the ability to degrade HIF, fail to overproduce TGF-α and proliferate in serum-free media. These data link HIF with the overproduction of a bona fide renal cell mitogen leading to activation of a pathway involved in growth of renal cancer cells. Moreover, our results suggest that HIF might be involved in oncogenesis to a much higher extent than previously appreciated.

UR - http://www.scopus.com/inward/record.url?scp=0242581718&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0242581718&partnerID=8YFLogxK

U2 - 10.1074/jbc.M305502200

DO - 10.1074/jbc.M305502200

M3 - Article

C2 - 12944410

AN - SCOPUS:0242581718

VL - 278

SP - 44966

EP - 44974

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 45

ER -