Differential expression of human Dlg in cervical intraepithelial neoplasias

Lin, Han-Ting; Steller, Michael A.; Aish, Leo; Hanada, Toshihiko; Chishti, Athar H.

doi:10.1016/j.ygyno.2004.01.025

Cited by 32 publications

(33 citation statements)

References 24 publications

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“…Studies in a number of different human cancers have now shown that loss of Scribble and Dlg is associated with more invasive and aggressive malignancies (Watson et al, 2002;Boussioutas et al, 2003;Cavatorta et al, 2004;Lin et al, 2004;Nakagawa et al, 2004;Navarro et al, 2005;Gardiol et al, 2006). It is now clear that Scribble plays a critical role in the regulation of directed cell migration during development and tissue homeostasis (e.g.…”

Section: Conserved Role For Scribble In Cell Migrationmentioning

confidence: 99%

The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge

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Kauffman

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et al. 2006

Oncogene

161

143

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Altered expression of human Scribble is associated with invasive epithelial cancers, however, its role in tumour development remains unclear. Mutations in Drosophila Scribble result in loss of polarity, overproliferation and 3D-tumourous overgrowth of epithelial cells. Using complementation studies in Drosophila we recently demonstrated that expression of human Scribble can also regulate polarity and restrict tissue overgrowth. Here, we have undertaken a detailed study of human Scribble function in the polarized mammary cell line, MCF10A. We show that although Scribble does not seem to be required for apical-basal polarity or proliferation control in MCF10A cells, Scribble is essential for the control of polarity associated with directed epithelial cell migration. Scribble-depleted MCF10A cells show defective in vitro wound closure and chemotactic movement. The cells at the wound edge fail to polarize, show reduced lamellipodia formation and impaired recruitment of Cdc42 and Rac1 to the leading edge. Furthermore, we show that this function is relevant in vivo as Scribble mutant mice show defective epidermal wound healing. This data identifies an essential role for mammalian Scribble in the regulation of the polarity specifically involved in directed epithelial migration.

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Section: Conserved Role For Scribble In Cell Migrationmentioning

confidence: 99%

The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge

Dow

Kauffman

Caddy³

et al. 2006

Oncogene

161

143

View full text Add to dashboard Cite

show abstract

“…Numerous recent reports have described that loss of Scribble and Dlg is correlated with late stage, aggressive epithelial tumours, including breast tumours (Massimi et al, 2004;Nakagawa et al, 2004;Navarro et al, 2005;Gardiol et al, 2006); however, there remains a seeming contradiction about the role of the Scribble-Dlg-Lgl complex in cancer progression. Dlg is known to be required for transformation by Ad9 E4-ORF1 (Frese et al, 2006) and Dlg is reported to have increased expression in low-grade tumours, but significantly decreased levels in high-grade cervical neoplasias (Lin et al, 2004). In addition, both Dlg and Scribble show increased expression in well-differentiated colon adenocarcinomas (Gardiol et al, 2006;Kamei et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling

et al. 2008

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Activating mutations in genes of the Ras-mitogenactivated protein kinase (MAPK) pathway occur in approximately 30% of all human cancers; however, mutation of Ras alone is rarely sufficient to induce tumour development. Scribble is a polarity regulator recently isolated from a Drosophila screen for events that cooperate with Ras mutation to promote tumour progression and cell invasion. In mammals, Scribble regulates directed cell migration and wound healing in vivo; however, no role has been identified for mammalian Scribble in oncogenic transformation. Here we show that in human epithelial cells expressing oncogenic Ras or Raf, loss of Scribble promotes invasion of cells through extracellular matrix in an organotypic culture system. Further, we show that the mechanism by which this occurs is in the regulation of MAPK signalling by Scribble. The suppression of MAPK signalling is a highly conserved function of Scribble as it also prevents Raf-mediated defects in Drosophila wing development. Our data identify Scribble as an important mediator of MAPK signalling and provide a molecular basis for the observation that Scribble expression is decreased in many invasive human cancers.

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“…Mutations in either of these genes in Drosophila result in the development of epithelial hyperplasia, loss of cell-cell contacts (38,39), and tumorigenesis of the imaginal discs and brain lobes (40). In the human cervix, both hDlg and hScrib are gradually altered in cellular localization and expression is lost as low-grade lesions progress to invasive cervical carcinomas (41)(42)(43). Reductions in hDlg and hScrib are also seen in human cervical cancer cell lines (19).…”

Section: Cancer Researchmentioning

confidence: 99%

The Human Papillomavirus E6 Oncogene Dysregulates the Cell Cycle and Contributes to Cervical Carcinogenesis through Two Independent Activities

et al. 2007

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Cervical cancer is a leading cause of death due to cancer among women worldwide. Using transgenic mice to dissect the contributions of the human papillomavirus (HPV) 16 E6 and E7 oncogenes in cervical cancer, E7 was identified previously to be the dominant oncogene. Specifically, when treated with exogenous estrogen for 6 months, E7 transgenic mice developed cancer throughout the reproductive tract, but E6 transgenic mice did not. E6 contributed to carcinogenesis of the reproductive tract, as E6/E7 double transgenic mice treated for 6 months with estrogen developed larger cancers than E7 transgenic mice. In the current study, we investigated whether the E6 oncogene alone could cooperate with estrogen to induce cervical cancer after an extended estrogen treatment period of 9 months. We found that the E6 oncogene synergizes with estrogen to induce cervical cancer after 9 months, indicating that E6 has a weaker but detectable oncogenic potential in the reproductive tract compared with the E7 oncogene. Using transgenic mice that express mutant forms of HPV16 E6, we determined that the interactions of E6 with cellular A-helix and PDZ partners correlate with its ability to induce cervical carcinogenesis. In analyzing the tumors arising in E6 transgenic mice, we learned that E6 induces expression of the E2F-responsive genes, Mcm7 and cyclin E, in the absence of the E7 oncogene. E6 also prevented the expression of p16 in tumors of the reproductive tract through a mechanism mediated by the interaction of E6 with

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Differential expression of human Dlg in cervical intraepithelial neoplasias

Cited by 32 publications

References 24 publications

The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge

The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge

Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling

The Human Papillomavirus E6 Oncogene Dysregulates the Cell Cycle and Contributes to Cervical Carcinogenesis through Two Independent Activities

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