Transport of hypoxia-inducible factor HIF-1α into the nucleus involves importins 4 and 7

Chachami, Georgia; Paraskeva, Efrosyni; Mingot, José-Manuel; Braliou, Georgia G.; Görlich, Dirk; Simos, George

doi:10.1016/j.bbrc.2009.09.093

Cited by 66 publications

(61 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Only a few proteins are known to be substrates of IPO4 (30,(38)(39)(40). Interestingly, one study suggests that the IPO4 ortholog Imp4 of Schistosoma mansoni, Escherichia coli, and yeast promotes cell survival in response to alkylating agents (41).…”

Section: Discussionmentioning

confidence: 99%

CCAAT/enhancer binding protein delta (C/EBPδ, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage

Wang

Sarkar

Zhou³

et al. 2010

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

View full text Add to dashboard Cite

Maintenance of genomic integrity is an essential cellular function. We previously reported that the transcription factor and tumor suppressor CCAAT/enhancer binding protein δ (C/EBPδ, CEBPD; also known as "NFIL-6β") promotes genomic stability. However, the molecular mechanism was not known. Here, we show that C/EBPδ is a DNA damage-induced gene, which supports survival of mouse bone marrow cells, mouse embryo fibroblasts (MEF), human fibroblasts, and breast tumor cells in response to the DNA cross-linking agent mitomycin C (MMC). Using gene knockout, protein depletion, and overexpression studies, we found that C/EBPδ promotes monoubiquitination of the Fanconi anemia complementation group D2 protein (FANCD2), which is necessary for its function in replication-associated DNA repair. C/EBPδ interacts with FANCD2 and importin 4 (IPO4, also known as "Imp4" and "RanBP4") via separate domains, mediating FANCD2-IPO4 association and augmenting nuclear import of FANCD2, a prerequisite for its monoubiquitination. This study identifies a transcription-independent activity of C/EBPδ in the DNA damage response that may in part underlie its tumor suppressor function. Furthermore, we report a function of IPO4 and nuclear import in the Fanconi anemia pathway of DNA repair.Fanconi anemia | DNA repair | mitomycin C | importin 4 | protein adaptor

show abstract

Section: Discussionmentioning

confidence: 99%

CCAAT/enhancer binding protein delta (C/EBPδ, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage

Wang

Sarkar

Zhou³

et al. 2010

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

View full text Add to dashboard Cite

show abstract

“…Recently, we and others studied the involvement of different nuclear transport receptors in regulation of the oxygen sensing pathway (Chachami et al, 2009;Depping et al, 2008). Moreover, we could demonstrate that nuclear import of PHD1 is importin-a/ b-dependent and relies on a nuclear localisation signal (NLS) (Steinhoff et al, 2009).…”

Section: Introductionmentioning

confidence: 93%

Oxygen sensing by Prolyl-4-Hydroxylase PHD2 within the nuclear compartment and the influence of compartimentalisation on HIF-1 signalling

Pientka

Schindler

et al. 2012

Journal of Cell Science

View full text Add to dashboard Cite

SummaryHypoxia-inducible factors (HIFs) regulate more than 200 genes involved in cellular adaptation to reduced oxygen availability. HIFs are heterodimeric transcription factors that consist of one of three HIF-a subunits and a HIF-b subunit. Under normoxic conditions the HIFa subunit is hydroxylated by members of a family of prolyl-4-hydroxylase domain (PHD) proteins, PHD1, PHD2 and PHD3, resulting in recognition by von-Hippel-Lindau protein, ubiquitylation and proteasomal degradation. It has been suggested that PHD2 is the key regulator of HIF-1a stability in vivo. Previous studies on the intracellular distribution of PHD2 have provided evidence for a predominant cytoplasmic localisation but also nuclear activity of PHD2. Here, we investigated functional nuclear transport signals in PHD2 and identified amino acids 196-205 as having a crucial role in nuclear import, whereas amino acids 6-20 are important for nuclear export. Fluorescence resonance energy transfer (FRET) showed that an interaction between PHD2 and HIF-1a occurs in both the nuclear and cytoplasmic compartments. However, a PHD2 mutant that is restricted to the cytoplasm does not interact with HIF-1a and shows less prolyl hydroxylase activity for its target HIF-1a than wild-type PHD2 located in the nucleus. Here, we present a new model by which PHD2-mediated hydroxylation of HIF-1a predominantly occurs in the cell nucleus and is dependent on very dynamic subcellular trafficking of PHD2.

show abstract

“…The time, however, that HIF-1 spends in the nucleus and, ultimately, its activity also depend on its nuclear import rate. Recent studies have shown that HIF-1 physically interacts with multiple import receptors, including members of the importin- family (Depping et al, 2008) and importins 4 and 7, which can mediate translocation of HIF-1 through nuclear pore complexes and its entry into the nucleoplasm (Chachami et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Casein kinase 1 regulates human hypoxia-inducible factor HIF-1

Kalousi

Mylonis

Politou

et al. 2010

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

Hypoxia-inducible factor 1 (HIF-1), a transcriptional activator that mediates cellular response to hypoxia and a promising target of anticancer therapy, is essential for adaptation to low oxygen conditions, embryogenesis and tumor progression. HIF-1 is a heterodimer of HIF-1α, expression of which is controlled by oxygen levels as well as by various oxygen-independent mechanisms, and HIF-1β (or ARNT), which is constitutively expressed. In this work, we investigate the phosphorylation of the N-terminal heterodimerization (PAS) domain of HIF-1α and identify Ser247 as a major site of in vitro modification by casein kinase 1δ (CK1δ). Mutation of this site to alanine, surprisingly, enhanced the transcriptional activity of HIF-1α, a result phenocopied by inhibition or small interfering RNA (siRNA)-mediated silencing of CK1δ under hypoxic conditions. Conversely, overexpression of CK1δ or phosphomimetic mutation of Ser247 to aspartate inhibited HIF-1α activity without affecting its stability or nuclear accumulation. Immunoprecipitation and in vitro binding experiments suggest that CK1-dependent phosphorylation of HIF-1α at Ser247 impairs its association with ARNT, a notion also supported by modeling the structure of the complex between HIF-1α and ARNT PAS-B domains. We suggest that modification of HIF-1α by CK1 represents a novel mechanism that controls the activity of HIF-1 during hypoxia by regulating the interaction between its two subunits.

show abstract

Transport of hypoxia-inducible factor HIF-1α into the nucleus involves importins 4 and 7

Cited by 66 publications

References 29 publications

CCAAT/enhancer binding protein delta (C/EBPδ, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage

CCAAT/enhancer binding protein delta (C/EBPδ, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage

Oxygen sensing by Prolyl-4-Hydroxylase PHD2 within the nuclear compartment and the influence of compartimentalisation on HIF-1 signalling

Casein kinase 1 regulates human hypoxia-inducible factor HIF-1

Contact Info

Product

Resources

About