PTCH1 gene polymorphisms in ovarian tumors: Potential protective role of c.3944T allele

Musani, Vesna; Sabol, Maja; Car, Diana; Ozretić, Petar; Kalafatić, Držislav; Maurac, Ivana; Orešković, Slavko; Levanat, Sonja

doi:10.1016/j.gene.2012.12.089

Cited by 8 publications

(14 citation statements)

References 45 publications

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“…51,52 Taken all together, our results showed that the number of CGG repeats, in the context of the complete 5'UTR, could not have a significant impact on either mRNA or protein expression of PTCH1b. While only alleles with a relatively small number of CGG repeats have been found (3 and 5 to 8), so far no unambiguous association of a certain number of CGG repeats with disease has been demonstrated, as noted in Musani et al 35 All these observations support the thesis that this PTCH1 polymorphism could not be a genetic background (a causal mutation) of a trinucleotide repeat disorder-like disease.…”

Section: Discussionmentioning

confidence: 83%

“…These repeat numbers were all found in healthy, control population. 35 Results of luciferase assays performed in transfected HCT116 p53C/C cells showed that the insertion of PTCH1b 5'UTR caused significant changes in Firefly luciferase (Fluc) activity compared to the empty plasmid (pGL3-P, based on the pGL3-Promoter Luciferase Reporter Vector) (P < 0.0001). The 188nt-long 5'UTR caused on average more than 2-fold increase in activity, while all alleles of the 300nt-long 5'UTR decreased luciferase activity around 5-fold.…”

Section: Resultsmentioning

confidence: 99%

“…35 Hence we constructed an additional pGL3-P-based plasmid harboring the 188nt-5'UTR (CGG) 6 repeats and tested it in MCF7 and HEK 293T cells (Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

“…In our previous research in patients with different types of ovarian neoplasms and healthy controls, we identified 2 additional alleles -(CGG) 5 , which was found in one healthy control sample, and (CGG) 6 allele, which was found in one ovarian cancer patient. 35 Since the initial discovery of this trinucleotide repeat variant, its proximity to the AUG codon suggested that the number of CGG repeats could affect the efficacy of 5'UTR in its regulatory role of PTCH1b expression. To address this issue, 2 functional analyses have been published so far.…”

Section: Discussionmentioning

confidence: 99%

“…35,73 For the alleles harboring 5, 7 and 8 CGG repeats we used genomic DNA from healthy control samples having (CGG) 5 /(CGG) 7 , (CGG) 7 /(CGG) 7 and (CGG) 8 /(CGG) 8 genotypes, respectively. For the allele with 6 CGG repeats we used a genomic DNA sample collected from an ovarian cancer patient with the (CGG) 6 /(CGG) 8 heterozygous genotype.…”

Section: Plasmid Constructionmentioning

confidence: 99%

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Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

et al. 2015

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Inga (2015) Regulation of human PTCH1b expression by different 5' untranslated region cis-regulatory elements, RNA Biology, 12:3, 290-304, DOI: 10.1080/15476286.2015 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.

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Section: Discussionmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

“…35 Hence we constructed an additional pGL3-P-based plasmid harboring the 188nt-5'UTR (CGG) 6 repeats and tested it in MCF7 and HEK 293T cells (Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Plasmid Constructionmentioning

confidence: 99%

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Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

et al. 2015

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PTCH1 gene variants rs357564, rs2236405, rs2297086 and rs41313327, mRNA and tissue expression in basal cell carcinoma patients from Western Mexico

Zambrano‐Román,

Padilla‐Gutiérrez,

Valle

et al. 2024

Clinical Laboratory Analysis

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BackgroundBasal cell carcinoma (BCC) represents about 80% of all cases of skin cancer. The PTCH1 is a transmembrane protein of the Sonic Hedgehog signaling pathway that regulates cell proliferation. Genetic variants in PTCH1 gene have been previously described in association with BCC development. In addition, PTCH1 mRNA and protein expression analysis are also significant to understand its role in skin cancer physiopathology.MethodsAn analytical cross‐sectional study was performed, and a total of 250 BCC patients and 290 subjects from the control group (CG) were included, all born in western Mexico. The genotypes and relative expression of the mRNA were determined by TaqMan® assay. The protein expression was investigated in 70 BCC paraffin‐embedded samples with PTCH1 antibodies. Semi‐quantitative analysis was performed to determine the expression level in the immunostained cells.ResultsWe did not find evidence of an association between PTCH1 rs357564, rs2297086, rs2236405, and rs41313327 genetic variants and susceptibility to BCC. Likewise, no statistically significant differences were found in the comparison of the mRNA level expression between BCC and CG (p > 0.05). The PTCH1 protein showed a low expression in 6 of the analyzed samples and moderate expression in 1 sample. No association was found between genetic variants, protein expression, and demographic‐clinical characteristics (p > 0.05).ConclusionThe studied PTCH1 variants may not be associated with BCC development in the Western Mexico population. The PTCH1 mRNA levels were lower in patients with BCC compared to the control group, but its protein was underexpressed in the tissue samples.

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Inherited rare and common variants in PTCH1 and PTCH2 contributing to the predisposition to reproductive cancers

Yang

Zhou

et al. 2022

Gene

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PTCH1 gene polymorphisms in ovarian tumors: Potential protective role of c.3944T allele

Cited by 8 publications

References 45 publications

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

PTCH1 gene variants rs357564, rs2236405, rs2297086 and rs41313327, mRNA and tissue expression in basal cell carcinoma patients from Western Mexico

Inherited rare and common variants in PTCH1 and PTCH2 contributing to the predisposition to reproductive cancers

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