PMID- 24416388
OWN - NLM
STAT- MEDLINE
DCOM- 20140902
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 1
DP  - 2014
TI  - Inflammatory conditions induce IRES-dependent translation of cyp24a1.
PG  - e85314
LID - 10.1371/journal.pone.0085314 [doi]
LID - e85314
AB  - Rapid alterations in protein expression are commonly regulated by adjusting 
      translation. In addition to cap-dependent translation, which is e.g. induced by 
      pro-proliferative signaling via the mammalian target of rapamycin (mTOR)-kinase, 
      alternative modes of translation, such as internal ribosome entry site 
      (IRES)-dependent translation, are often enhanced under stress conditions, even if 
      cap-dependent translation is attenuated. Common stress stimuli comprise nutrient 
      deprivation, hypoxia, but also inflammatory signals supplied by infiltrating 
      immune cells. Yet, the impact of inflammatory microenvironments on translation in 
      tumor cells still remains largely elusive. In the present study, we aimed at 
      identifying translationally deregulated targets in tumor cells under inflammatory 
      conditions. Using polysome profiling and microarray analysis, we identified 
      cyp24a1 (1,25-dihydroxyvitamin D3 24-hydroxylase) to be translationally 
      upregulated in breast tumor cells co-cultured with conditioned medium of 
      activated monocyte-derived macrophages (CM). Using bicistronic reporter assays, 
      we identified and validated an IRES within the 5' untranslated region (5'UTR) of 
      cyp24a1, which enhances translation of cyp24a1 upon CM treatment. Furthermore, 
      IRES-dependent translation of cyp24a1 by CM was sensitive to 
      phosphatidyl-inositol-3-kinase (PI3K) inhibition, while constitutive activation 
      of Akt sufficed to induce its IRES activity. Our data provide evidence that 
      cyp24a1 expression is translationally regulated via an IRES element, which is 
      responsive to an inflammatory environment. Considering the negative feedback 
      impact of cyp24a1 on the vitamin D responses, the identification of a novel, 
      translational mechanism of cyp24a1 regulation might open new possibilities to 
      overcome the current limitations of vitamin D as tumor therapeutic option.
FAU - Rubsamen, Daniela
AU  - Rubsamen D
AD  - Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 
      Frankfurt, Germany.
FAU - Kunze, Michael M
AU  - Kunze MM
AD  - Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 
      Frankfurt, Germany.
FAU - Buderus, Victoria
AU  - Buderus V
AD  - Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 
      Frankfurt, Germany.
FAU - Brauss, Thilo F
AU  - Brauss TF
AD  - Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 
      Frankfurt, Germany.
FAU - Bajer, Magdalena M
AU  - Bajer MM
AD  - Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 
      Frankfurt, Germany.
FAU - Brune, Bernhard
AU  - Brune B
AD  - Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 
      Frankfurt, Germany.
FAU - Schmid, Tobias
AU  - Schmid T
AD  - Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 
      Frankfurt, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140108
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (5' Untranslated Regions)
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 1.14.- (Steroid Hydroxylases)
RN  - EC 1.14.15.16 (CYP24A1 protein, human)
RN  - EC 1.14.15.16 (Vitamin D3 24-Hydroxylase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - 5' Untranslated Regions
MH  - Base Sequence
MH  - Cell Line, Tumor
MH  - Culture Media, Conditioned/chemistry/*pharmacology
MH  - Female
MH  - Gene Expression Profiling
MH  - *Gene Expression Regulation, Neoplastic
MH  - Genes, Reporter
MH  - Humans
MH  - Inflammation/genetics/metabolism/pathology
MH  - Macrophages/cytology/metabolism
MH  - Molecular Sequence Data
MH  - Oligonucleotide Array Sequence Analysis
MH  - Phosphatidylinositol 3-Kinases/genetics/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Biosynthesis/*drug effects
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - Ribosomes/*drug effects
MH  - Signal Transduction
MH  - Steroid Hydroxylases/*genetics/metabolism
MH  - Vitamin D3 24-Hydroxylase
PMC - PMC3885688
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/01/15 06:00
MHDA- 2014/09/03 06:00
PMCR- 2014/01/08
CRDT- 2014/01/14 06:00
PHST- 2013/07/01 00:00 [received]
PHST- 2013/12/04 00:00 [accepted]
PHST- 2014/01/14 06:00 [entrez]
PHST- 2014/01/15 06:00 [pubmed]
PHST- 2014/09/03 06:00 [medline]
PHST- 2014/01/08 00:00 [pmc-release]
AID - PONE-D-13-27103 [pii]
AID - 10.1371/journal.pone.0085314 [doi]
PST - epublish
SO  - PLoS One. 2014 Jan 8;9(1):e85314. doi: 10.1371/journal.pone.0085314. eCollection 
      2014.