Regulation of tyrosine hydroxylase promoter activity by the von Hippel–Lindau tumor suppressor protein and hypoxia‐inducible transcription factors

Schnell, Per-Olof; Ignacak, Monika; Bauer, Amy L.; Striet, Justin B.; Paulding, Waltke R.; Czyzyk-Krzeska, Maria F.

doi:10.1046/j.1471-4159.2003.01696.x

Cited by 101 publications

(104 citation statements)

References 42 publications

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“…Hypoxia induces TH mRNA expression in rat mesencephalic cultures (Leclere et al, 2004), whereas HIF-1␣ contributes to induction of TH transcription in PC12 cells (Schnell et al, 2003). Our findings indicate that HIF-1␣ represents an important factor for in vitro neuronal and dopaminergic differentiation, as well.…”

Section: Discussionsupporting

confidence: 54%

Lack of Hypoxia-Inducible Factor-1α Impairs Midbrain Neural Precursor Cells Involving Vascular Endothelial Growth Factor Signaling

Milošević¹,

Maisel²,

Wegner³

et al. 2007

J. Neurosci.

108

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Oxygen tension is critical for proliferation of human and murine midbrain-derived neural precursor cells (mNPCs). Here, we conditionally inactivated the hypoxia-responsive transcription factor hypoxia-inducible factor-1␣ (HIF-1␣) in murine NPCs to determine its role in proliferation, survival, and dopaminergic differentiation in vitro as well as survival of murine dopaminergic neurons in vivo. HIF-1␣ conditional knock-out (HIF-1␣ CKO) mNPCs showed midbrain-specific impairment of survival and proliferation. Dopaminergic differentiation of HIF-1␣ CKO mNPCs in vitro was markedly reduced. Expression of vascular endothelial growth factor (VEGF) mRNA was reduced in HIF-1␣ CKO mNPCs, whereas erythropoietin signaling was not affected. Treatment of HIF-1␣ CKO mNPCs with 50 ng/ml VEGF partially recovered proliferation and dopaminergic differentiation in vitro. In substantia nigra (SN) of adult HIF-1␣ CKO mice, protein levels of dopaminergic marker molecules such as tyrosine hydroxylase (TH) and aldehyde dehydrogenase were reduced by 41 and 61%, respectively. The cell survival marker Bcl-2 was reduced by 58% while caspase-3 was activated. Nonbiased stereological cell counts of TH-positive neurons in SN of young adult HIF-1␣ CKO mice revealed a reduction of 31% compared with cre/wt mice (in which the wildtype Hif1a allele is expressed in parallel with the Cre recombinase allele). However, we found no impairment of striatal dopamine concentrations or locomotor behavior. In conclusion, HIF-1␣ seems to be a transcription factor relevant to the development and survival of substantia nigra dopaminergic neurons involving VEGF signaling.

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Section: Discussionsupporting

confidence: 54%

Lack of Hypoxia-Inducible Factor-1α Impairs Midbrain Neural Precursor Cells Involving Vascular Endothelial Growth Factor Signaling

Milošević¹,

Maisel²,

Wegner³

et al. 2007

J. Neurosci.

108

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“…In cultures of E14 rat primary (mesencephalic) neurons and PC12 cells, hypoxia increases tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis (37,38). In addition, embryonic precursors from both the peripheral nervous system and the central nervous system exhibit enhanced neuronal proliferation and differentiation in response to lowered oxygen tension (6,39).…”

Section: Discussionmentioning

confidence: 99%

Endogenous Erythropoietin Signaling Is Required for Normal Neural Progenitor Cell Proliferation

Chen

Asavaritikrai

Prchal

et al. 2007

Journal of Biological Chemistry

161

138

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Erythropoietin (Epo) and its receptor (EpoR), critical for erythropoiesis, are expressed in the nervous system. Prior to death in utero because of severe anemia EpoR-null mice have fewer neural progenitor cells, and differentiated neurons are markedly sensitive to hypoxia, suggesting that during development Epo stimulates neural cell proliferation and prevents neuron apoptosis by promoting oxygen delivery to brain or by direct interaction with neural cells. Here we present evidence that neural progenitor cells express EpoR at higher levels compared with mature neurons; that Epo stimulates proliferation of embryonic neural progenitor cells; and that endogenous Epo contributes to neural progenitor cell proliferation and maintenance. EpoRnull mice were rescued with selective EpoR expression driven by the endogenous EpoR promoter in hematopoietic tissue but not in brain. Although these mice exhibited normal hematopoiesis and erythrocyte production and survived to adulthood, neural cell proliferation and viability were affected. Embryonic brain exhibited increased neural cell apoptosis, and neural cell proliferation was reduced in the adult hippocampus and subventricular zone. Neural cells from these animals were more sensitive to hypoxia/glutamate neurotoxicity than normal neurons in culture and in vivo. These observations demonstrate that endogenous Epo/EpoR signaling promotes cell survival in embryonic brain and contributes to neural cell proliferation in adult brain in regions associated with neurogenesis. Therefore, Epo exerts extrahematopoietic function and contributes directly to brain development, maintenance, and repair by promoting cell survival and proliferation independent of insult, injury, or ischemia.

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“…Immunoblots were performed with the following antibodies: Akt pS473, S6K1 pT389, Akt, S6K1, and cytochrome c from Cell Signaling Technology; Pten, Actin, Bax, and FOXO3a from Santa Cruz Biotechnology. HIF-1α blots were performed as described (34). Contrast, brightness, and levels adjustments were performed in Canvas and Photoshop software (ACDSee; Adobe).…”

Section: Methodsmentioning

confidence: 99%

Requirement for ribosomal protein S6 kinase 1 to mediate glycolysis and apoptosis resistance induced by Pten deficiency

Tandon

Gallo

Khatri

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Pten inactivation promotes cell survival in leukemia cells by activating glycolytic metabolism. We found that targeting ribosomal protein S6 kinase 1 (S6K1) in Pten-deficient cells suppressed glycolysis and induced apoptosis. S6K1 knockdown decreased expression of HIF-1α, and HIF-1α was sufficient to restore glycolysis and survival of cells lacking S6K1. In the Pten fl/fl Mx1-Cre + mouse model of leukemia, S6K1 deletion delayed the development of leukemia. Thus, S6K1 is a critical mediator of glycolytic metabolism, cell survival, and leukemogenesis in Pten-deficient cells.

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Regulation of tyrosine hydroxylase promoter activity by the von Hippel–Lindau tumor suppressor protein and hypoxia‐inducible transcription factors

Cited by 101 publications

References 42 publications

Lack of Hypoxia-Inducible Factor-1α Impairs Midbrain Neural Precursor Cells Involving Vascular Endothelial Growth Factor Signaling

Lack of Hypoxia-Inducible Factor-1α Impairs Midbrain Neural Precursor Cells Involving Vascular Endothelial Growth Factor Signaling

Endogenous Erythropoietin Signaling Is Required for Normal Neural Progenitor Cell Proliferation

Requirement for ribosomal protein S6 kinase 1 to mediate glycolysis and apoptosis resistance induced by Pten deficiency

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