Article

Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein.

Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, S-171 77 Stockholm, Sweden.
The EMBO Journal (Impact Factor: 10.75). 09/2000; 19(16):4298-309. DOI: 10.1093/emboj/19.16.4298
Source: PubMed

ABSTRACT In normoxic cells the hypoxia-inducible factor-1 alpha (HIF-1 alpha) is rapidly degraded by the ubiquitin-proteasome pathway, and activation of HIF-1 alpha to a functional form requires protein stabilization. Here we show that the product of the von Hippel-Lindau (VHL) tumor suppressor gene mediated ubiquitylation and proteasomal degradation of HIF-1 alpha under normoxic conditions via interaction with the core of the oxygen-dependent degradation domain of HIF-1 alpha. The region of VHL mediating interaction with HIF-1 alpha overlapped with a putative macromolecular binding site observed within the crystal structure of VHL. This motif of VHL also represents a mutational hotspot in tumors, and one of these mutations impaired interaction with HIF-1 alpha and subsequent degradation. Interestingly, the VHL binding site within HIF-1 alpha overlapped with one of the minimal transactivation domains. Protection of HIF-1 alpha against degradation by VHL was a multistep mechanism, including hypoxia-induced nuclear translocation of HIF-1 alpha and an intranuclear hypoxia-dependent signal. VHL was not released from HIF-1 alpha during this process. Finally, stabilization of HIF-1 alpha protein levels per se did not totally bypass the need of the hypoxic signal for generating the transactivation response.

0 Bookmarks
 · 
102 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The gastrointestinal mucosa has proven to be an interesting tissue for which to investigate disease-related metabolism. In this review, we outline some evidence that implicates metabolic signaling as important features of barrier in the healthy and disease. Studies from cultured cell systems, animal models and human patients have revealed that metabolites generated within the inflammatory microenvironment are central to barrier regulation. These studies have revealed a prominent role for hypoxia and hypoxia-inducible factor (HIF) at key steps in adenine nucleotide metabolism and within the creatine kinase pathway. Results from animal models of intestinal inflammation have demonstrated an almost uniformly beneficial influence of HIF stabilization on disease outcomes and barrier function. Studies underway to elucidate the contribution of immune responses will provide additional insight into how metabolic changes contribute to the complexity of the gastrointestinal tract and how such information might be harnessed for therapeutic benefit.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite recent advances in cancer therapies, metastatic renal cell carcinoma (RCC) remains difficult to treat. Most RCCs result from inactivation of the von Hippel Lindau (VHL) tumor suppressor, leading to stable expression of Hypoxia-Inducible Factor-alpha (HIF-1 alpha, -2 alpha, -3 alpha) and the induction of downstream target genes, including those responsible for angiogenesis and metastasis. While VHL is inactivated in the majority of RCC cases, expression of the PTEN tumor suppressor is reduced in about 30% of cases. PTEN functions to antagonize PI3K/Akt/ mTOR signaling, thereby controlling cell growth and survival. Activation of PI3K/Akt/mTOR leads to increased HIF-1 alpha expression in certain cancer cells, supporting the rationale of using mTOR inhibitors as anti-cancer agents. Notably, HIF-2 alpha, rather than HIF-1 alpha, has been shown to play a critical role in renal tumorigenesis. To investigate whether HIF-2 alpha is similarly regulated by the PI3K pathway in VHL(-/)-RCC cells, we manipulated PI3K signaling using PTEN overexpression and siRNA knockdown studies and pharmacologic inhibition of PI3K or Akt. Our data support a novel role for wild-type PTEN in promoting HIF-2 alpha activity in VHL null RCC cells. This mechanism is unique to the cellular environment in which HIF-2 alpha expression is deregulated, resulting from the loss of VHL function. Our data show that PTEN induces HIF-2 alpha transcriptional activity by inhibiting expression of Yin Yang 1 (YY1), which acts as a novel corepressor of HIF-2a. Further, PTEN suppression of YY1 is mediated through antagonism of PI3K signaling. We conclude that wild-type PTEN relieves the repressive nature of YY1 at certain HIF-2 alpha target promoters and that this-mechanism may promote early renal tumorigenesis resulting from VHL inactivation by increasing HIF-2 alpha activity.
    Cancer biology & therapy 10/2014; 8(14):1389-1401. DOI:10.4161/cbt.8.14.8880 · 3.63 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Macrophages accumulate in poorly vascularised and hypoxic sites including solid tumours, wounds and sites of infection and inflammation where they can be exposed to low levels of oxygen for long periods. Up to date, different studies have shown that a number of transcription factors are activated by hypoxia which in turn activate a broad array of mitogenic, pro-invasive, pro-angiogenic, and pro-metastatic genes. On the other hand, macrophages respond to hypoxia by up-regulating several genes which are chief factors in angiogenesis and tumorigenesis. Therefore, in this review article we focus mainly on the role of macrophages during inflammation and discuss their response to hypoxia by regulating a diverse array of transcription factors. We also review the existing literatures on hypoxia and its cellular and molecular mechanism which mediates macrophages activation.
    Iranian Journal of Basic Medical Sciences 11/2014; 17(11):820-30.

Full-text

Download
58 Downloads
Available from
May 30, 2014