Unknown

Dataset Information

0

Tumor suppressor gene co-operativity in compound Patched1 and suppressor of fused heterozygous mutant mice.

ABSTRACT: Dysregulation of the Hedgehog signaling pathway is central to the development of certain tumor types, including medulloblastoma and basal cell carcinoma (BCC). Patched1 (Ptch1) and Suppressor of fused (Sufu) are two essential negative regulators of the pathway with tumor suppressor activity. Ptch1(+/-) mice are predisposed to developing medulloblastoma and rhabdomyosarcoma, while Sufu(+/-) mice develop a skin phenotype characterized by basaloid epidermal proliferations. Here, we have studied tumor development in Sufu(+/-)Ptch1(+/-) mice to determine the effect of compound heterozygosity on the onset, incidence, and spectrum of tumors. We found significantly more (2.3-fold) basaloid proliferations in Sufu(+/-)Ptch1(+/-) compared to Sufu(+/-) female, but not male, mice. For medulloblastoma, the cumulative 1-yr incidence was 1.5-fold higher in Sufu(+/-)Ptch1(+/-) compared to Ptch1(+/-) female mice but this strong trend was not statistically significant. Together this suggests a weak genetic interaction of the two tumor suppressor genes. We noted a few rhabdomyosarcomas and pancreatic cysts in the Sufu(+/-)Ptch1(+/-) mice, but the numbers were not significantly different from the single heterozygous mice. Hydrocephalus developed in approximately 20% of the Ptch1(+/-) and Sufu(+/-)Ptch1(+/-) but not in Sufu(+/-) mice. Interestingly, most of the medulloblastomas from the Sufu(+/-)Ptch1(+/-) mice had lost expression of the remaining Ptch1 wild-type allele but not the Sufu wild-type allele. On the contrary, Sufu as well as Gli1 and Gli2 expression was upregulated in the medulloblastomas compared to adult cerebellum in Ptch1(+/-) and Sufu(+/-)Ptch1(+/-) mice. This suggests that Sufu expression may be regulated by Hedgehog pathway activity and could constitute another negative feedback loop in the pathway.

SUBMITTER: Svard J 

PROVIDER: S-EPMC2674531 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

Tumor suppressor gene co-operativity in compound Patched1 and suppressor of fused heterozygous mutant mice.

Svärd Jessica J   Rozell Björn B   Toftgård Rune R   Teglund Stephan S  

Molecular carcinogenesis 20090501 5

Dysregulation of the Hedgehog signaling pathway is central to the development of certain tumor types, including medulloblastoma and basal cell carcinoma (BCC). Patched1 (Ptch1) and Suppressor of fused (Sufu) are two essential negative regulators of the pathway with tumor suppressor activity. Ptch1(+/-) mice are predisposed to developing medulloblastoma and rhabdomyosarcoma, while Sufu(+/-) mice develop a skin phenotype characterized by basaloid epidermal proliferations. Here, we have studied tum  ...[more]

Similar Datasets

Unknown Alterations in Morphology and Adult Neurogenesis in the Dentate Gyrus of Patched1 Heterozygous Mice.
| S-EPMC5974030 | biostudies-literature
Unknown Compound Heterozygous <i>KCNQ1</i> Mutations Causing Recessive Romano-Ward Syndrome: Functional Characterization by Mutant Co-expression.
| S-EPMC7937651 | biostudies-literature
Unknown Tumor suppressor genes promote rhabdomyosarcoma progression in p53 heterozygous, HER-2/neu transgenic mice.
| S-EPMC3960193 | biostudies-literature
Unknown Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions.
| S-EPMC5193403 | biostudies-literature
Unknown Cas9-mediated allelic exchange repairs compound heterozygous recessive mutations in mice.
| S-EPMC6126964 | biostudies-literature
Unknown Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice.
| S-EPMC4717204 | biostudies-literature
Unknown Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice.
| S-EPMC1472405 | biostudies-literature
Unknown Synergistic epistasis enhances the co-operativity of mutualistic interspecies interactions.
| S-EPMC8319347 | biostudies-literature
Unknown Multicontact Co-operativity in Spike-Timing-Dependent Structural Plasticity Stabilizes Networks.
| S-EPMC6041941 | biostudies-literature
Unknown Computer simulation of assembly and co-operativity of hexameric AAA ATPases.
| S-EPMC3711915 | biostudies-literature