Transduction pathways involved in Hypoxia-Inducible Factor-1 phosphorylation and activation

Minet, Emmanuel; Michel, G.; Mottet, Denis; Raes, Martine; Michiels, Carine

doi:10.1016/s0891-5849(01)00657-8

Cited by 161 publications

(119 citation statements)

References 58 publications

Supporting

Mentioning

112

Contrasting

Unclassified

Order By: Relevance

“…Hypoxia-inducible factor 1a (HIF-1a), a key molecule that facilitates the process of angiogenesis in RCC, is a well-documented substrate of ERK in several different cell types. 41,42 The cooperativity of HIF-1a and pERK-1/2 may explain the high vascular nature of RCC tumors per se and hence the correlation between pERK-1/2 and tumor size observed in our current study. Consistent with this view, a recent study has shown that the specific pharmacologic inhibition of ERK is sufficient to suppress the growth and angiogenesis of RCC tumor human xenografts in mice.…”

Section: Discussionmentioning

confidence: 71%

Activated extracellular signal‐regulated kinase is an independent prognostic factor in clinically confined renal cell carcinoma

Campbell

Nuttall

Griffiths

et al. 2009

Cancer

View full text Add to dashboard Cite

BACKGROUND: Extracellular signal‐regulated kinase (ERK) promotes proliferation, metastasis, and poor survival in cancers of the breast, lung, and liver. Advanced localized renal cell carcinoma (RCC) is extraordinarily treatment resistant and has high recurrence rates despite surgery. Limited data exist regarding the prognostic significance of activated (phosphorylated) ERK in RCC. The authors hypothesized that activated ERK (pERK) promotes disease progression and metastasis in localized RCC and may be of value as a biomarker to predict disease recurrence. METHODS: The expression profile of pERK was examined by immunocytochemistry using a tissue microarray constructed from 174 drug treatment–naive patients who had undergone radical nephrectomy for localized RCC. Levels of tumor‐cell specific pERK were scored and correlated with clinicopathologic parameters of RCC and disease‐free survival. RESULTS: Immunostaining for pERK was present in 36% of all RCCs, with a predominance found in the clear cell histologic subtype. High expression was associated with increased tumor size, increased TNM stage, and vascular invasion. Patients with pERK‐positive tumors had a mean disease‐free survival of 4.19 years, compared with 6.38 years for patients with pERK‐negative tumors (P < .001). Cox regression models revealed pERK to be a significant independent predictor of disease‐free survival, with a hazards score of 2.9 (P < .001), a value similar to tumor grade (hazards ratio, 3.01; P < .001). CONCLUSIONS: Expression of pERK is an independent prognostic factor in RCC that is associated with advanced and aggressive pathologic features of renal tumors and predicts the onset of metastasis in patients with localized disease. Cancer 2009. © 2009 American Cancer Society.

show abstract

Section: Discussionmentioning

confidence: 71%

Activated extracellular signal‐regulated kinase is an independent prognostic factor in clinically confined renal cell carcinoma

Campbell

Nuttall

Griffiths

et al. 2009

Cancer

View full text Add to dashboard Cite

show abstract

“…These observations are of special interest, given the current controversy as to whether HIF-1a should be regarded as a pro-or an antiapoptotic protein. 21 Although this study has not addressed the mechanisms governing the antiapoptotic effect of HIF-1a in the context of hypoxic or A/R-mediated injury, other investigators have shown that the induction of HIF-1a protein and its transcriptional activation by hypoxia and oxidative stress are regulated by several signaling pathways including PI3K/AKT/FRAP [30][31][32] p38, and ERK kinase 30,32,33 in which the redox-sensitive factors Ref-1 and thioredoxin and the Rho family small GTPase Rac1 have been shown to play a role. 31,33,34 Moreover, protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators has been shown to relate to enhanced DNA binding of HIF-1a and ATF-1/CREB transcription factors and to increased expression of glycolytic enzymes.…”

Section: Discussionmentioning

confidence: 95%

Antiapoptotic action of hypoxia-inducible factor-1α in human endothelial cells

Liu

et al. 2004

Laboratory Investigation

View full text Add to dashboard Cite

Hypoxia-inducible factor-1 (HIF-1) is the major transcription factor involved in the adaptive response to hypoxia and consists of HIF-1a and HIF-1b subunits. Indirect evidence suggests that HIF-1a may exert both proapoptotic and antiapoptotic actions in response to hypoxia. In this study, we evaluated the effects of RNA interference (RNAi) targeting HIF-1a messenger RNA (mRNA) on apoptosis in primary cultured human umbilical vascular endothelial cells (HUVECs) exposed to anoxia and reoxygenation (A/R). HUVECs were transfected with specific 21-nt small interfering RNA (siRNA) duplexes targeting HIF-1a mRNA sequences or scrambled RNA duplexes and subjected either to normoxia for 251/2 h or to anoxia for 11/2 h, and subsequently normoxia for 24 h (A/R). Control samples were subjected to A/R but not transfected. HUVECs apoptosis was evaluated by Tdt-mediated dUTP nick end-labeling (TUNEL) assay and by activated caspase-3 immunostaining and immunoblotting. The efficacy of RNAi was assessed by knockdown of HIF-1a mRNA and protein expression via in situ hybridization, real-time quantitative PCR, immunohistochemistry, and Western blotting. When compared with normoxic cultures, A/R significantly upregulated HIF-1a mRNA and protein expression in HUVECs, but did not appreciably alter the percentage of apoptotic cells. In contrast, a significantly greater proportion of HUVECs transfected with specific siRNA duplexes and exposed to A/R demonstrated evidence of apoptosis when compared with nontransfected cells. Transfection with specific siRNA duplexes knocked down HIF-1a mRNA and protein expression in A/R-treated cells by approximately 60%, whereas transfection with scrambled siRNA duplexes had no noticeable effect on HIF-1a expression. These findings strongly suggest that HIF-1a exerts an antiapoptotic role in HUVECs stressed by anoxia.

show abstract

“…Mice received morphine and placebo through pellet implantation method as described 19 with a few modifications. Briefly, 75 mg morphine pellets, placebo, and/or 30 mg Naltrexone pellets (National Institutes of Health [NIH]/ National Institute on Drug Abuse [NIDA], Bethesda, MD) were inserted in a small pocket created by a small incision on the animal's dorsal side; incisions were resealed using surgical wound clips (Stoelting, 9 mm Stainless Steel, Wooddale, IL).…”

Section: In Vivomentioning

confidence: 99%

Morphine Suppresses Tumor Angiogenesis through a HIF-1α/p38MAPK Pathway

Koodie

Ramakrishnan

Roy

2010

The American Journal of Pathology

114

View full text Add to dashboard Cite

Morphine, a highly potent analgesic agent, is frequently prescribed for moderate to severe cancer pain. In this study, morphine was administered at a clinically relevant analgesic dose to assess tumor cell-induced angiogenesis and subcutaneous tumor growth in nude mice using mouse Lewis lung carcinoma cells (LLCs). Implantation of mice with a continuous slow-release morphine pellet achieved morphine plasma levels within 250 -400 ng/ml (measured using a radioimmunoassay, Coat-ACount Serum Morphine) and was sufficient to significantly reduce tumor cell-induced angiogenesis and tumor growth when compared with placebo treatment. Morphometric analysis for blood vessel formation further confirmed that morphine significantly reduced blood vessel density (P < 0.003), vessel branching (P < 0.05), and vessel length (P < 0.002) when compared with placebo treatment. Morphine's effect was abolished in mice coadministered the classical opioid receptor antagonist, naltrexone, and in mu-opioid receptor knockout mice, supporting the involvement of the classical opioid receptors in vivo. Morphine's inhibitory effect is mediated through the suppression of the hypoxia-induced mitochondrial p38 mitogen-activated protein kinase (MAPK) pathway. Our results suggest that in vitro morphine treatment of LLCs inhibits the hypoxia-induced nuclear translocation of hypoxiainducible transcription factor 1␣ to reduce vascular endothelial growth factor transcription and secretion, in a manner similar to pharmacological blockade with the p38 MAPK-specific inhibitor, SB203585. These studies indicate that morphine, in addition to its analgesic function , may be exploited for its antiangiogenic potential. Pain management is a serious problem in patients with cancer. Morphine is considered the "gold standard" for relieving pain and is currently one of the most effective drugs available clinically for the management of moderate to severe pain associated with cancer.

show abstract

Transduction pathways involved in Hypoxia-Inducible Factor-1 phosphorylation and activation

Cited by 161 publications

References 58 publications

Activated extracellular signal‐regulated kinase is an independent prognostic factor in clinically confined renal cell carcinoma

Activated extracellular signal‐regulated kinase is an independent prognostic factor in clinically confined renal cell carcinoma

Antiapoptotic action of hypoxia-inducible factor-1α in human endothelial cells

Morphine Suppresses Tumor Angiogenesis through a HIF-1α/p38MAPK Pathway

Contact Info

Product

Resources

About