Patched2 Modulates Tumorigenesis in Patched1 Heterozygous Mice

Lee, Youngsoo; Miller, Heather Lee; Russell, H. R.; Boyd, Kelli L.; Curran, Tom; McKinnon, Peter J.

doi:10.1158/0008-5472.can-06-0505

Cited by 102 publications

(103 citation statements)

References 43 publications

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“…Similar to the triple mutant mice, DNA ligase IVmutant mice also exhibit medulloblastoma (Lee and McKinnon, 2002) and based on our observations, medulloblastoma in DNA ligase IV-mutant mice is also likely caused by Rag-independent DNA damage. Even though our observations are similar to those described for the dna ligase IV…”

Section: Discussionsupporting

confidence: 77%

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Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs

et al. 2006

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Ku80 maintains the genome by repairing DNA doublestrand breaks (DSBs) through nonhomologous end joining (NHEJ), a pathway that repairs nonspecific DSBs and Rag-1 Rag-2 (Rag)-specific DSBs. As a result, Ku80 deletion results in phenotypes characteristic of defective repair for both nonspecific DSBs (c-radiation hypersensitivity and genomic instability) and Rag-specific DSBs (immunodeficiency). ku80 À/À mice also exhibit neuronal apoptosis, but we do not know the type of DSBs responsible for this response. In spite of genomic instability and immunodeficiency, cancer incidence is not increased in ku80 À/À mice. However, deletion of the tumor suppressor, p53 greatly increases pro-B-cell lymphoma in ku80 À/À mice due to IgH/c-Myc translocations suggesting that responses to Rag-specific DNA DSBs suppress cancer. Like suppression of pro-B-cell lymphoma, neuronal apoptosis requires p53 presenting the intriguing possibility that Rag-specific DSBs mediate neuronal development as they do lymphocyte development. Here we delete Rag-1 from ku80À/À mice to differentiate the impact nonspecific vs Rag-specific DSBs have on ku80 À/À mice. We find that deleting Rag-1 prevents pro-B cell lymphoma confirming Rag-induced DSBs induce this form of cancer. Both the triple mutant mice and the p53 À/À rag-1 À/À mice exhibit T-cell lymphoma and medulloblastoma; incidence of T-cell lymphoma is the same for both cohorts whereas incidence of medulloblastoma is higher for the triple-mutant cohort. Thus, p53-mediated neuronal apoptosis likely suppresses medulloblastoma in Ku80-deleted mice and Ku80 likely suppresses medulloblastoma by repairing nonspecific DNA DSBs instead of Rag-specific DSBs. Our observations are the first to show that Ku80 suppresses cancer caused by nonspecific DNA damage and we present a novel mouse model for medulloblastoma.

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Section: Discussionsupporting

confidence: 77%

“…À/À mice exhibit medulloblastoma by 9 weeks (Lee and McKinnon, 2002) again indicating that deletion of both DNA damage responses and NHEJ-proteins is important for increasing cancer incidence. However, we do not know if increased medulloblastoma is due to defective repair of either nonspecific or Rag-induced DSBs.…”

Section: Introductionmentioning

confidence: 99%

Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs

et al. 2006

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“…These transcriptional changes ultimately resolve to produce normally patterned HH-responsive tissues, although aged male Ptch2 +/− and Ptch2 −/− mice develop epidermal hyperplasia and alopecia (Nieuwenhuis et al, 2006). That PTCH1 action may mask PTCH2 activity is a reasonable hypothesis, especially given the observation that the loss of Ptch2 enhances tumorigenesis in a Ptch1 +/− background (Lee et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning

et al. 2013

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SUMMARYHedgehog (HH) signaling is essential for vertebrate and invertebrate embryogenesis. In Drosophila, feedback upregulation of the HH receptor Patched (PTC; PTCH in vertebrates), is required to restrict HH signaling during development. By contrast, PTCH1 upregulation is dispensable for early HH-dependent patterning in mice. Unique to vertebrates are two additional HH-binding antagonists that are induced by HH signaling, HHIP1 and the PTCH1 homologue PTCH2. Although HHIP1 functions semi-redundantly with PTCH1 to restrict HH signaling in the developing nervous system, a role for PTCH2 remains unresolved. Data presented here define a novel role for PTCH2 as a ciliary localized HH pathway antagonist. While PTCH2 is dispensable for normal ventral neural patterning, combined removal of PTCH2-and PTCH1-feedback antagonism produces a significant expansion of HH-dependent ventral neural progenitors. Strikingly, complete loss of PTCH2-, HHIP1-and PTCH1-feedback inhibition results in ectopic specification of ventral cell fates throughout the neural tube, reflecting constitutive HH pathway activation. Overall, these data reveal an essential role for liganddependent feedback inhibition of vertebrate HH signaling governed collectively by PTCH1, PTCH2 and HHIP1.

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“…However, PTCH2 cannot repress activation of the HH signaling pathway and Ptch2 knockout mice do not show significant phenotypes (Lee et al, 2006). On the other hand, PTCH1 inhibits HH signaling activation and Ptch1 null mice die during embryogenesis (Goodrich et al, 1997;Hahn et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Distinct roles of first exon variants of the tumor-suppressor Patched1 in Hedgehog signaling

et al. 2007

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Patched1 (PTCH1) is one of the key molecules involved in the Hedgehog (HH) signaling pathway and acts as the receptor of HH ligands. Additionally, PTCH1 inhibits the positive signal transductor Smoothened (SMO). Several PTCH1 splice variants are known but the functional differences among them are not clear. Here, we demonstrate the unique biological properties of the PTCH1 isoforms generated by alternative first exon usage. All isoforms examined worked as functional receptors of both Sonic HH and Desert HH. However, the signaling upregulated isoforms PTCH1-1B and -1C inhibited SMO and the pathway transcription factors glioma 1 (GLI1) and GLI2 to a higher extent than PTCH1-1 and -1Ckid. Moreover, in situ hybridizations allowed the detection of the Ptch1 isoforms in specific structures of the developing mouse embryo. Additionally, the differences in the N-terminal tail had a dramatic influence on the steady states of the proteins, with PTCH1-1B and -1C levels being significantly higher than PTCH1-1 and -1Ckid. This implies that the pronounced signaling inhibitory properties of PTCH1-1B and -1C may be mostly due to this high-protein expression rather than to intrinsic functional differences. Thus, our study supports a role of splicing variation and promoter choice for HH signaling regulation.

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Patched2 Modulates Tumorigenesis in Patched1 Heterozygous Mice

Abstract: The sonic hedgehog (SHH) receptor Patched

Cited by 102 publications

References 43 publications

Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs

Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs

Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning

Distinct roles of first exon variants of the tumor-suppressor Patched1 in Hedgehog signaling

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