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Manisterski M.,Dana Childrens Hospital | Golan M.,Prostate Cancer Research Laboratory | Amir S.,Prostate Cancer Research Laboratory | Weisman Y.,Dana Childrens Hospital | And 2 more authors.
Cell Cycle | Year: 2010

Parathyroid hormone-related protein (PTHrP) expressed by human cancer cells enhances tumor cell growth and metastasis in vivo and it is considered as the major factor responsible for humoral hypercalcemia of malignancy. Hypoxia is a widespread feature of most solid tumors. Here, we studied the effects of hypoxia on PTHrP expression. We found that PTHrP is transcriptionally induced by prolonged (48 h) hypoxia in multiple human cancer and endothelial cell lines. Pharmacological up or downregulation of hypoxia-inducible factor (HIF) resulted in induction or reduction of PTHrP levels, respectively, implying that PTHrP hypoxic induction is mediated by HIF pathway. Analysis of PTHrP promoter revealed that both HIF-1α and HIF-2α subunits bind to specific hypoxia-responsive elements (HRE) within the P2 promoter of PTHrP. However, only HIF-2α can drive direct transcriptional activation, which can be abolished by mutation in the specific HRE. To the best of our knowledge, these results provide for the first time evidence that PTHrP is regulated by hypoxia in cancer and endothelial cells through the HIF-2 pathway. We suggest that HIF-2 induced by intratumoral hypoxia or by other genetic alterations may contribute to the pathogenesis of hypercalcemia of malignancy and cancer aggressiveness by stimulation of PTHrP expression. © 2010 Landes Bioscience.

Golan M.,Prostate Cancer Research Laboratory | Mabjeesh N.J.,Prostate Cancer Research Laboratory
Cell Cycle | Year: 2013

Septin 9 isoform 1 (SEPT9-i1) protein associates with hypoxia-inducible factor (HIF)-1α to augment HIF-1 transcriptional activity. The first 25 amino acids of SEPT9-i1 (N25) are unique compared with other members of the mammalian septin family. This N25 domain is critical for HIF-1 activation by SEPT9-i1 but not essential for the protein-protein interaction. Here, we show that expression of N25 induces a significant dose-dependent inhibition of HIF-1 transcriptional activity under normoxia and hypoxia without influencing cellular HIF-1α protein levels. In vivo, N25 expression inhibits proliferation, tumor growth and angiogenesis concomitant with decreased expression levels of intratumoral HIF-1 downstream genes. Depletion of endogenous SEPT9-i1 or the exogenous expression of N 25 fragment reduces nuclear HIF-1α levels accompanied by reciprocal accumulation of HIF-1α in the cytoplasm. Mechanistically, SEPT9-i1 binds to importin-α through N25 depending on its bipartite nuclear localization signal, to scaffold the association between HIF-1α and importin-α, which leads to facilitating HIF-1α nuclear translocation. Our data explore a new and a previously unrecognized role of a septin protein in the cytoplasmic-nuclear translocation process. This new level in the regulation of HIF-1α translocation is critical for efficient HIF-1 transcriptional activation that could be targeted for cancer therapeutics. © 2013 Landes Bioscience .

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