PMID- 25826662
OWN - NLM
STAT- MEDLINE
DCOM- 20151217
LR  - 20201113
IS  - 1555-8584 (Electronic)
IS  - 1547-6286 (Print)
IS  - 1547-6286 (Linking)
VI  - 12
IP  - 3
DP  - 2015
TI  - Regulation of human PTCH1b expression by different 5' untranslated region 
      cis-regulatory elements.
PG  - 290-304
LID - 10.1080/15476286.2015.1008929 [doi]
AB  - PTCH1 gene codes for a 12-pass transmembrane receptor with a negative regulatory 
      role in the Hedgehog-Gli signaling pathway. PTCH1 germline mutations cause Gorlin 
      syndrome, a disorder characterized by developmental abnormalities and tumor 
      susceptibility. The autosomal dominant inheritance, and the evidence for PTCH1 
      haploinsufficiency, suggests that fine-tuning systems of protein patched homolog 
      1 (PTC1) levels exist to properly regulate the pathway. Given the role of 5' 
      untranslated region (5'UTR) in protein expression, our aim was to thoroughly 
      explore cis-regulatory elements in the 5'UTR of PTCH1 transcript 1b. The (CGG)n 
      polymorphism was the main potential regulatory element studied so far but with 
      inconsistent results and no clear association between repeat number and disease 
      risk. Using luciferase reporter constructs in human cell lines here we show that 
      the number of CGG repeats has no strong impact on gene expression, both at mRNA 
      and protein levels. We observed variability in the length of 5'UTR and changes in 
      abundance of the associated transcripts after pathway activation. We show that 
      upstream AUG codons (uAUGs) present only in longer 5'UTRs could negatively 
      regulate the amount of PTC1 isoform L (PTC1-L). The existence of an internal 
      ribosome entry site (IRES) observed using different approaches and mapped in the 
      region comprising the CGG repeats, would counteract the effect of the uAUGs and 
      enable synthesis of PTC1-L under stressful conditions, such as during hypoxia. 
      Higher relative translation efficiency of PTCH1b mRNA in HEK 293T cultured 
      hypoxia was observed by polysomal profiling and Western blot analyses. All our 
      results point to an exceptionally complex and so far unexplored role of 5'UTR 
      PTCH1b cis-element features in the regulation of the Hedgehog-Gli signaling 
      pathway.
FAU - Ozretic, Petar
AU  - Ozretic P
AD  - a Laboratory for Hereditary Cancer ; Division of Molecular Medicine ; Ruder 
      Boskovic Institute ; Zagreb , Croatia.
FAU - Bisio, Alessandra
AU  - Bisio A
FAU - Musani, Vesna
AU  - Musani V
FAU - Trnski, Diana
AU  - Trnski D
FAU - Sabol, Maja
AU  - Sabol M
FAU - Levanat, Sonja
AU  - Levanat S
FAU - Inga, Alberto
AU  - Inga A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - RNA Biol
JT  - RNA biology
JID - 101235328
RN  - 0 (5' Untranslated Regions)
RN  - 0 (Internal Ribosome Entry Sites)
RN  - 0 (PTCH1 protein, human)
RN  - 0 (Patched Receptors)
RN  - 0 (Patched-1 Receptor)
RN  - 0 (Protein Isoforms)
RN  - 0 (Receptors, Cell Surface)
SB  - IM
MH  - *5' Untranslated Regions
MH  - Base Sequence
MH  - Cell Hypoxia/genetics
MH  - *Gene Expression Regulation
MH  - HCT116 Cells
MH  - HEK293 Cells
MH  - Humans
MH  - *Internal Ribosome Entry Sites
MH  - MCF-7 Cells
MH  - Molecular Sequence Data
MH  - Patched Receptors
MH  - Patched-1 Receptor
MH  - *Protein Biosynthesis
MH  - Protein Isoforms/genetics/metabolism
MH  - Receptors, Cell Surface/*genetics/metabolism
MH  - Ribosomes/genetics/metabolism
MH  - Signal Transduction
PMC - PMC4615190
OTO - NOTNLM
OT  - 5'UTR
OT  - 5'UTR, 5' untranslated region
OT  - CGG repeats
OT  - Fluc, Firefly luciferase
OT  - Hedgehog-Gli
OT  - Hh-Gli, Hedgehog-Gli
OT  - IRES
OT  - IRES, internal ribosome entry site
OT  - POL, polysome-associated
OT  - PTC1-L, protein patched homolog 1
OT  - PTCH1
OT  - Rluc, Renilla luciferase
OT  - SUB, subpolysomal
OT  - isoform L PTCH1b, Patched 1 gene, transcript variant 1b
OT  - uAUG
OT  - uAUG, upstream AUG codon
OT  - uORF
OT  - uORF, upstream open reading frame
EDAT- 2015/04/01 06:00
MHDA- 2015/12/19 06:00
PMCR- 2016/03/31
CRDT- 2015/04/01 06:00
PHST- 2015/04/01 06:00 [entrez]
PHST- 2015/04/01 06:00 [pubmed]
PHST- 2015/12/19 06:00 [medline]
PHST- 2016/03/31 00:00 [pmc-release]
AID - 1008929 [pii]
AID - 10.1080/15476286.2015.1008929 [doi]
PST - ppublish
SO  - RNA Biol. 2015;12(3):290-304. doi: 10.1080/15476286.2015.1008929.