Unbalanced overexpression of the mutant allele in murine Patched mutants

Calzada‐Wack, Julia; Kappler, Roland; Schnitzbauer, Udo; Richter, Thomas; Nathrath, Michaela; Rosemann, Michael; Wagner, Stephan N.; Hein, Rüdiger; Hahn, Heidi

doi:10.1093/carcin/23.5.727

Cited by 43 publications

(40 citation statements)

References 19 publications

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“…Heterozygous p53 þ /À mutant mice develop a number of sarcomas, including RMS (Harvey et al, 1993;Jacks et al, 1994). RMS are also prevalent in heterozygous Ptch1 neo67/ þ animals (Calzada-Wack et al, 2002). We show that the RMS encountered in these mice differ in their gene expression patterns and investigate the link between these profiles and their genetic etiology.…”

Section: Introductionmentioning

confidence: 77%

“…Quantitative real-time PCR was carried out using an ABI PRISM 7700 sequence detector (Applied Biosystems, Foster City, CA, USA) as previously described (Calzada-Wack et al, 2002). Gene-specific primers were 5 0 -TCTCCTCCCCTCAAT AAGCTATTC-3 0 and 5 0 -TGGCGCTGACCCACAACT-3 0 for amplification of murine p53, 5 0 -GGAACATCTCAGGG CCGAA-3 0 and 5 0 -GCAGAAGACCAATCTGCGCTT-3 0 for amplification of murine p21 cip1/waf1 , and 5 0 -GTGCTCAAG GCCCTGTGC-3 0 and 5 0 -CAGACAAGCAGCCGCTCAC-3 0 for amplification of murine Bax1.…”

Section: Reverse Transcription-pcrmentioning

confidence: 99%

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Profiling the molecular difference between Patched- and p53-dependent rhabdomyosarcoma

et al. 2004

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Rhabdomyosarcoma (RMS) is a highly malignant tumor that is histologically related to skeletal muscle, yet genetic and molecular lesions underlying its genesis and progression remain largely unknown. In this study we have compared the molecular profiles of two different mouse models of RMS, each associated with a defined primary genetic defect known to play a role in rhabdomyosarcomagenesis in man. We report that RMS of heterozygous Patched1 (Ptch1) mice show less aggressive growth and a greater degree of differentiation than RMS of heterozygous p53 mice. By means of cDNA microarray analysis we demonstrate that RMS in Ptch1 mutants predominantly express a number of myogenic markers, including myogenic differentiation 1, myosin heavy chain, actin, troponin and tropomyosin, as well as genes associated with Hedgehog/Patched signaling like insulin-like growth factor 2, forkhead box gene Foxf1 and the growth arrest and DNA-damage-inducible gene Gadd45a. In sharp contrast, RMS in p53 mutants display higher expression levels of cell cycle-associated genes like cyclin B1, cyclindependent kinase 4 and the proliferation marker Ki-67. These results demonstrate that different causative mutations lead to distinct gene expression profiles in RMS, which appear to reflect their different biological characteristics. Our results provide a first step towards a molecular classification of different forms of RMS. If the described differences can be confirmed in human RMS our results will contribute to a new molecular taxonomy of this cancer, which will be critical for gene mutation-and expression-specific therapy.

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Section: Introductionmentioning

confidence: 77%

Section: Reverse Transcription-pcrmentioning

confidence: 99%

Profiling the molecular difference between Patched- and p53-dependent rhabdomyosarcoma

et al. 2004

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“…Tumors of this animal model lack the expression of wt Ptch alleles and are therefore deficient in Ptch (13,17). Starting points of the daily intraperitoneal treatment with 100 ng/kg calcitriol or vehicle were day 0 or 60 after BCC induction.…”

Section: Ert2mentioning

confidence: 99%

Antitumoral Effects of Calcitriol in Basal Cell Carcinomas Involve Inhibition of Hedgehog Signaling and Induction of Vitamin D Receptor Signaling and Differentiation

Uhmann

Niemann

Lammering

et al. 2011

Molecular Cancer Therapeutics

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Activation of the Hedgehog (Hh)-signaling pathway due to deficiency in the Hh receptor Patched1 (Ptch) is the pivotal defect leading to formation of basal cell carcinoma (BCC). Recent reports provided evidence of Ptch-dependent secretion of vitamin D 3 -related compound, which functions as an endogenous inhibitor of Hh signaling by repressing the activity of the signal transduction partner of Ptch, Smoothened (Smo). This suggests that Ptch-deficient tumor cells are devoid of this substance, which in turn results in activation of Hhsignaling. Here, we show that the application of the physiologically active form of vitamin D 3, calcitriol, inhibits proliferation and growth of BCC of Ptch mutant mice in vitro and in vivo. This is accompanied by the activation of the vitamin D receptor (Vdr) and induction of BCC differentiation. In addition, calcitriol inhibits Hh signaling at the level of Smo in a Vdr-independent manner. The concomitant antiproliferative effects on BCC growth are stronger than those of the Hh-specific inhibitor cyclopamine, even though the latter more efficiently inhibits Hh signaling. Taken together, we show that exogenous supply of calcitriol controls the activity of 2 independent pathways, Hh and Vdr signaling, which are relevant to tumorigenesis and tumor treatment. These data suggest that calcitriol could be a therapeutic option in the treatment of BCC, the most common tumor in humans. Mol Cancer Ther; 10(11); 2179-88. Ó2011 AACR.

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“…Rapid induction of BCCs was observed in transgenic mice overexpressing Shh (Oro et al, 1997). Overexpression of SMO was also found in most BCCs (Kallassy et al, 1997) while haploinsufficiency of PTC was shown to induce medulloblastoma (Zurawel et al, 2000) and rhabdomyosarcoma in mice (Calzada-Wack et al, 2002).…”

mentioning

confidence: 99%

Alteration of the PATCHED locus in superficial bladder cancer

et al. 2003

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Chromosome 9 alterations are the most frequently encountered cytologic anomalies in urothelial carcinoma (UC). We previously screened 139 low-stage UCs for loss of heterozygosity on chromosome 9, and identified five distinct regions likely to harbour tumour-suppressor genes. The present study focused on deletion mapping in the 9q22 region with 11 additional microsatellite markers. New deletions in the 9q22 region were found in five tumours. Deletion mapping allowed us to identify a 0.5 CM common minimal region of deletion between markers D9S280 and D9S1809, encompassing PATCHED (PTC), a gene identified as a tumour suppressor in basal cell carcinoma and in medulloblastoma. A marker located in the first intron of this gene showed the highest percentage of deletion (45%). cDNA sequencing in 15 tumours with deletion of PTC showed no mutation in the remaining allele. However, average expression of PTC mRNA measured by semiquantitative RT-PCR was significantly decreased in tumours with LOH in the 9q22 region, compared to normal urothelium (P ¼ 0.04), while it showed marked fluctuations in tumours without deletion. Our results suggest that the PTC gene is a putative suppressor at the 9q22 locus and that haploinsufficiency of this gene may be an early event in the development of papillary bladder tumours.

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Unbalanced overexpression of the mutant allele in murine Patched mutants

Cited by 43 publications

References 19 publications

Profiling the molecular difference between Patched- and p53-dependent rhabdomyosarcoma

Profiling the molecular difference between Patched- and p53-dependent rhabdomyosarcoma

Antitumoral Effects of Calcitriol in Basal Cell Carcinomas Involve Inhibition of Hedgehog Signaling and Induction of Vitamin D Receptor Signaling and Differentiation

Alteration of the PATCHED locus in superficial bladder cancer

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