Targeted Disruption of Smad4 in Mouse Epidermis Results in Failure of Hair Follicle Cycling and Formation of Skin Tumors

Yang, Leilei; Mao, Chunming; Teng, Yan; Li, Wenlong; Zhang, Jishuai; Chen, Xuan; Li, Xiaobing; Han, Xiuxin; Xia, Zenan; Deng, Hongkui; Yang, Xiao

doi:10.1158/0008-5472.can-05-0800

Cited by 97 publications

(133 citation statements)

References 43 publications

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“…In mice, loss of Smad4 results in early embryonic lethality because of impaired extraembryonic membrane formation and decreased epiblast proliferation (Sirard et al, 1998;Yang et al, 1998), whereas Smad4 heterozygous mice developed gastric polyposis and cancer because of haploinsufficiency (Takaku et al, 1999;Xu et al, 2000). Using tissue-specific knockout of Smad4 (Yang et al, 2002), we, along with others, showed that Smad4 deficiency could cause tumor formation in mammary tissue (Li et al, 2003), skin (Yang et al, 2005;Qiao et al, 2006), liver , forestomach (Teng et al, 2006) and colon (Kim et al, 2006). A recent study revealed that loss of Smad4 alone does not initiate pancreatic cancer formation, although it accelerates tumor formation on activation of oncogenic signaling, such as Kras (Izeradjene et al, 2007).…”

Section: Introductionmentioning

confidence: 64%

Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice

Ehdaie

Ohara

et al. 2009

Oncogene

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Mutations of SMAD4/DPC4 are found in about 60% of human invasive pancreatic ductal adenocarcinomas (PDACs); yet, the manner in which SMAD4 deficiency enhances tumorigenesis remains elusive. Using a CreLoxP approach, we generated a mutant mouse carrying a targeted deletion of Smad4 in the pancreas. We showed that the absence of Smad4 alone did not trigger pancreas tumor formation; however, it increased the expression of an inactivated form of Pten, suggesting a role of Pten in preventing Smad4-/-cells from undergoing malignancy. To investigate this, we disrupted both Pten and Smad4. We showed that Pten deficiency initiated widespread premalignant lesions, and a low tumor incidence that was significantly accelerated by Smad4-deficiency. The absence of Smad4 in a Pten-mutant background enhanced cell proliferation and triggered transdifferentiation from acinar, centroacinar and islet cells, accompanied by activation of Notch1 signaling. We showed that all tumors developed in the Smad4/Pten-mutant pancreas exhibited high levels of pAKT and mTOR, and that about 50 and 83% of human pancreatic cancers examined showed increased pAKT and pmTOR, respectively. Besides the similarity in gene expression, the pAKT and/or pmTORpositive human PDACs and mouse pancreatic tumors also shared some histopathological similarities. These observations indicate that Smad4/Pten-mutant mice mimic the tumor progression of human pancreatic cancers that are driven by activation of the AKT-mTOR pathway, and uncovered a synergistic action of Smad4 and Pten in repressing pancreatic tumorigenesis.

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Section: Introductionmentioning

confidence: 64%

Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice

Ehdaie

Ohara

et al. 2009

Oncogene

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“…To clarify whether or not Ppm1a-deficient keratinocytes, but not other cell types, mainly accounted for the delayed re-epithelialization observed in Ppm1a Ϫ/Ϫ mice, we generated keratinocyte-specific Ppm1a mutant (K5-Cre;Ppm1a fl/fl ) mice by breeding Ppm1a fl/fl mice with K5-Cre transgenic mice (29,30). Dramatic reduction of Ppm1a was demonstrated in the isolated Ppm1a mutant primary keratinocytes (supplemental Fig.…”

Section: Deletion Of Ppm1a Led To Delayed Re-epithelialization Duringmentioning

confidence: 99%

Delayed Re-epithelialization in Ppm1a Gene-deficient Mice Is Mediated by Enhanced Activation of Smad2

Yang

Teng²,

Hou³

et al. 2011

Journal of Biological Chemistry

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Background:The in vivo function of Ppm1a in mammals remains unknown. Results: Mice lacking Ppm1a developed normally but showed delayed re-epithelialization with retarded keratinocyte migration caused by overactivation of Smad2 during cutaneous wound healing. Conclusion: Ppm1a, through suppressing Smad2-mediated signaling, plays a critical role in re-epithelialization. Significance: We provided the first direct and critical genetic evidence of the in vivo role of Ppm1a.

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“…19 Skin-specific disruption of Smad4 results in increased epidermal proliferation consequently leading to squamous cell carcinoma formation. 20,21 Antitumor activity of BMPs may also be regulated by extracellular BMP inhibitors: expression of the BMP antagonist gremlin increased in basal cell carcinomas, in which gremlin promotes and BMPs inhibit cell proliferation. 22 However, mechanisms and downstream targets that mediate tumor suppressor function of the BMP signaling pathway in skin remain to be explored.…”

mentioning

confidence: 99%

Bone Morphogenetic Protein Antagonist Noggin Promotes Skin Tumorigenesis via Stimulation of the Wnt and Shh Signaling Pathways

Sharov

Mardaryev

Sharova

et al. 2009

The American Journal of Pathology

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Bone morphogenetic proteins (BMPs) play pivotal roles in the regulation of skin development. To study the role of BMPs in skin tumorigenesis, BMP antagonist noggin was used to generate keratin 14-targeted transgenic mice. In contrast to wild-type mice, transgenic mice developed spontaneous hair follicle-derived tumors, which resemble human trichofolliculoma. Global gene expression profiles revealed that in contrast to anagen hair follicles of wild-type mice, Skin cancer is the most common cancer in the United States, Europe, and other countries, and the incidence continues to increase. 1 During the last decade, considerable progress has been achieved in identification of molecular mechanisms underlying the development of the major cutaneous cancers, such as malignant melanoma, basal cell carcinoma, and squamous cell carcinoma. 2,3 In particular, it was shown that mechanisms controlling skin development and carcinogenesis appear to be very similar, and key signaling pathways (Wnt, hedgehog, notch, transforming growth factor-␤, etc) that regulate skin development are also implicated in the pathobiology of cutaneous neoplasias [reviewed in [1][2][3][4][5] ].Bone morphogenetic protein (BMP) signaling plays pivotal roles in the control of cutaneous development and also possesses a potent antitumor activity in postnatal skin [for review see 6,7 ]. BMP signaling is activated by binding of the BMP ligands to BMP receptors (BMPRs) followed by activation of the BMP-Smad and/or BMP-MAP kinase pathways.

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Targeted Disruption of Smad4 in Mouse Epidermis Results in Failure of Hair Follicle Cycling and Formation of Skin Tumors

Cited by 97 publications

References 43 publications

Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice

Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice

Delayed Re-epithelialization in Ppm1a Gene-deficient Mice Is Mediated by Enhanced Activation of Smad2

Bone Morphogenetic Protein Antagonist Noggin Promotes Skin Tumorigenesis via Stimulation of the Wnt and Shh Signaling Pathways

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