Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice

Xu, Xiaoling; Brodie, Steven G.; Yang, Xiao; Im, Young Hyuck; Parks, W. Tony; Chen, Lin; Zhou, Yong; Weinstein, Michael; Kim, S.-J.; Deng, Chu‐Xia

doi:10.1038/sj.onc.1203504

Cited by 220 publications

(171 citation statements)

References 45 publications

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“…In about 10-20% of colorectal tumors, DPC4 undergoes mutation (Hadzija et al, 2004). Also, it has been shown that Smad4 þ /À heterozygous mice develop inflammatory gastric polyps and tumors at about 12 months of age, with loss of the wild-type Smad4 allele (Xu et al, 2000). These tumors show moderate stromal cell proliferation, infiltration by eosinophils and plasma cells, as well as foci of adenocarcinoma with signet ring cells.…”

Section: Introductionmentioning

confidence: 99%

Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression

Katuri

Tang

et al. 2006

Oncogene

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Inactivation of the transforming growth factor-b (TGF-b) pathway occurs often in malignancies of the gastrointestinal (GI) system. However, only a fraction of sporadic GI tumors exhibit inactivating mutations in early stages of cancer formation, suggesting that other mechanisms play a critical role in the inactivation of this pathway. Here, we show a wide range of GI tumors, including those of the stomach, liver and colon in elf þ /À and elf þ /À /Smad4 þ /À mutant mice. We found that embryonic liver fodrin (ELF), a b-Spectrin originally identified in endodermal stem/ progenitor cells committed to foregut lineage, possesses potent antioncogenic activity and is frequently inactivated in GI cancers. Specifically, E-cadherin accumulation at cell-cell contacts and E-cadherin-b-catenin-dependent epithelial cell-cell adhesion is disrupted in elf þ /À / Smad4 þ /À mutant gastric epithelial cells, and could be rescued by ectopic expression of full-length elf, but not Smad3 or Smad4. Subcellular fractionation revealed that E-cadherin is expressed mainly at the cell membrane after TGF-b stimulation. In contrast, elf þ /À /Smad4 þ /À mutant tissues showed abnormal distribution of E-cadherin that could be rescued by overexpression of ELF but not Smad3 or Smad4. Our results identify a group of common lethal malignancies in which inactivation of TGF-b signaling, which is essential for tumor suppression, is disrupted by inactivation of the ELF adaptor protein.

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Section: Introductionmentioning

confidence: 99%

Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression

Katuri

Tang

et al. 2006

Oncogene

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“…It was recently reported that loss of one copy of a gene without any alteration in the remaining wild-type allele, a phenomenon referred to as haploinsufficiency, may be sufficient to promote cancer in many instances. Such is the case with the PTEN gene in solid renal cell carcinomas (Velickovic et al, 2002), SMAD4 in gastric cancers (Xu et al, 2000;Maurice et al, 2001) and p27 in various other cancers (Fero et al, 1998;Philipp-Staheli et al, 2001). Our data raise the possibility that haploinsufficiency of PTC may be involved in early UC, at least in tumours with LOH of the PTC marker.…”

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confidence: 81%

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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“…Using the Cre-loxP-mediated tissue specific knockout approach to overcome embryonic lethality, we showed that mice lacking Smad4 in their mammary glands displayed abnormal differentiation of mammary epithelium and tumorigenesis (Li et al, 2003b). Meanwhile, Smad4 heterozygous mice developed gastric polyposis and cancer (Redman et al, 2005;Takaku et al, 1999;Xu et al, 2000), and one out of 16 Smad4 þ /À mice also developed squamous cell carcinomas (SCCs) of the skin (Redman et al, 2005), suggesting that Smad4 also functions as a tumor suppressor in the mouse.…”

Section: Introductionmentioning

confidence: 99%

Hair follicle defects and squamous cell carcinoma formation in Smad4 conditional knockout mouse skin

et al. 2005

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Smad4 is the common mediator for TGFb signals, which play important functions in many biological processes. To study the role of Smad4 in skin development and epidermal tumorigenesis, we disrupted this gene in skin using the Cre-loxP approach. We showed that absence of Smad4 blocked hair follicle differentiation and cycling, leading to a progressive hair loss of mutant (MT) mice. MT hair follicles exhibited diminished expression of Lef1, and increased proliferative cells in the outer root sheath. Additionally, the skin of MT mice exhibited increased proliferation of basal keratinocytes and epidermal hyperplasia. Furthermore, we provide evidence that the absence of Smad4 resulted in a block of both TGFb and bone morphogenetic protein (BMP) signaling pathways, including p21, a well-known cyclin-dependent kinase inhibitor. Consequently, all MT mice developed spontaneous malignant skin tumors from 3 months to 13 months of age. The majority of tumors are malignant squamous cell carcinomas. A most notable finding is that tumorigenesis is accompanied by inactivation of phosphatase and tensin homolog deleted on chromosome 10 (Pten), activation of AKT, fast proliferation and nuclear accumulation of cyclin D1. These observations revealed the essential functions of Smad4-mediated signals in repressing skin tumor formation through the TGFb/BMP pathway, which interacts with the Pten signaling pathway.

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Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice

Cited by 220 publications

References 45 publications

Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression

Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression

Alteration of the PATCHED locus in superficial bladder cancer

Hair follicle defects and squamous cell carcinoma formation in Smad4 conditional knockout mouse skin

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