The Regulation of Hypoxic Genes by Calcium Involves c-Jun/AP-1, Which Cooperates with Hypoxia-Inducible Factor 1 in Response to Hypoxia

Salnikow, Konstantin; Kluz, Thomas; Costa, Max; Piquemal, David; Demidenko, Zoya N.; Xie, Keping; Blagosklonny, Mikhail V.

doi:10.1128/mcb.22.6.1734-1741.2002

Cited by 186 publications

(163 citation statements)

References 29 publications

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“…This similarity between calcium and hypoxia regulation might be important for understanding how hypoxia induces involucrin. For example, Salnikow et al (2002) have described an HIF-1a independent pathway for the hypoxia induction of AP-1 regulated genes in which hypoxia-induced intracellular calcium release and subsequent interaction at AP-1 promoter sites are key events. Calcium ion concentration is known to increase in the outer layers of stratified epithelia (Denda et al, 2000) and it is conceivable that hypoxia interacts with calcium ions to stimulate the production of involucrin and other AP-1-dependent proteins.…”

Section: Discussionmentioning

confidence: 99%

Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas

Azuma

et al. 2004

Br J Cancer

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The majority of hypoxic cells in squamous cell carcinomas of the head and neck and cervix express involucrin, a molecular marker for differentiation. This raises the question of whether involucrin is an oxygen-regulated protein and, if so, whether it could serve as an endogenous marker for tumour hypoxia. Consistent with oxygen regulation, involucrin protein was found to increase with increasing hypoxia in confluent cultures of moderately differentiated human SCC9 cells. Cells harvested at the point of confluence and exposed to graded concentrations of oxygen revealed a K m of approximately 15 mmHg for involucrin induction. This is similar to K m s for HIF1a, CAIX and VEGF. Involucrin induction showed a steep dependence on pO 2 with a transition from minimum to maximum expression occurring over less than an order of magnitude change in pO 2 . In contrast to SCC9 cells, involucrin was not induced by hypoxia in poorly differentiated SCC4 cells. It is concluded that involucrin is an oxygen-regulated protein, but that differentiation modulates its transcription status with respect to hypoxia induction.

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Section: Discussionmentioning

confidence: 99%

Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas

Azuma

et al. 2004

Br J Cancer

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“…Salnikow et al 2,5 showed that the enhancement of Cap43 gene expression by hypoxia or nickel was dependent on HIF-1 expression because such enhancement was absent in HIF-1␣-deficient mouse fibroblast cells. VHL-dependent downregulation of the Cap43 gene might be associated with HIF-mediated transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4] Induction of the Cap43 gene by hypoxia or nickel could be blocked by coadministration of calcium chelators, suggesting the involvement of free intracellular calcium. 2 Moreover, Salnikow et al 2,5 reported that the enhancement of Cap43 gene expression by hypoxia or nickel is dependent on hypoxia-inducible factor (HIF)-1 expression because such enhancement is absent in HIF-1 (-/-) cells.…”

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confidence: 99%

Downregulation of Cap43 gene by von Hippel‐Lindau tumor suppressor protein in human renal cancer cells

Masuda

Ono

Okamoto

et al. 2003

Intl Journal of Cancer

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We previously identified 9 genes (i.e., thymosin ␤4, secreted protein acidic and rich in cysteine, Cap43, ceruloplasmin, serum amyloid A, heat shock protein 90, LOT1, osteopontin and casein kinase I␥) that are more highly expressed in cancerous regions than in noncancerous regions in human renal cancers. In our study, we considered the possibility that the von Hippel-Lindau (VHL) tumor suppressor gene might be able to affect the expression of these 9 genes in renal cancer cells. We first

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“…N-myc downstream-regulated gene 1 (NDRG1) is a recently described protein that is induced by cellular stress, in particular, it is significantly upregulated by hypoxia through HIF-1-dependent and -independent mechanisms (Park et al, 2000;Salnikow et al, 2000;Salnikow et al, 2002;Karaczyn et al, 2005). Other stressinducing agents, such as homocysteine and tunicamycin (Kokame et al, 1996), nickel compounds (Zhou et al, 1998), synthetic retinoids (Piquemal et al, 1999) and compounds that lead to cellular differentiation (van Belzen et al, 1997) can also modulate its expression.…”

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confidence: 99%

Cellular differentiation determines the expression of the hypoxia-inducible protein NDRG1 in pancreatic cancer

et al. 2006

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N-myc downstream-regulated gene-1 (NDRG1) is a recently described hypoxia-inducible protein that is upregulated in various human cancers. Pancreatic ductal adenocarcinoma, called pancreatic cancer, is a highly aggressive cancer that is characterised by its avascular structure, which results in a severe hypoxic environment. In this study, we investigated whether NDRG1 is upregulated in these tumours, thus providing a novel marker for malignant cells in the pancreas. By immunohistochemistry, we observed that NDRG1 was highly expressed in well-differentiated cells of pancreatic cancer, whereas the poorly differentiated tumour cells were negative. In addition, hyperplastic islets and ducts of nonquiescent pancreatic tissue were positive. To further explore its selective expression in tumours, two well-established pancreatic cancer cell lines of unequal differentiation status were exposed to 2% oxygen. NDRG1 mRNA and protein were upregulated by hypoxia in the moderately differentiated Capan-1 cells; however, its levels remained unchanged in the poorly differentiated Panc-1 cell line. Taken together, our data suggest that NDRG1 will not serve as a reliable marker of tumour cells in the pancreas, but may serve as a marker of differentiation. Furthermore, we present the novel finding that cellular differentiation may be an important factor that determines the hypoxia-induced regulation of NDRG1.

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The Regulation of Hypoxic Genes by Calcium Involves c-Jun/AP-1, Which Cooperates with Hypoxia-Inducible Factor 1 in Response to Hypoxia

Cited by 186 publications

References 29 publications

Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas

Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas

Downregulation of Cap43 gene by von Hippel‐Lindau tumor suppressor protein in human renal cancer cells

Cellular differentiation determines the expression of the hypoxia-inducible protein NDRG1 in pancreatic cancer

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