Specific down-modulation of Notch1 signaling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late steps of malignant transformation.
The Notch family of cell surface receptors plays a key role in cell-fate determination and differentiation, functioning in a cell- and context-specific manner. In mammalian cells, Notch activation is generally thought to maintain stem cell potential and inhibit differentiation, thereby promoting carcinogenesis. However, in other contexts such as primary epithelial cells (keratinocytes), increased Notch activity causes exit from the cell cycle and/or commitment to differentiation. We now report that expression of the endogenous Notch1 gene is markedly reduced in a panel of cervical carcinoma cells whereas expression of Notch2 remains elevated, and Notch1 expression is similarly reduced or absent in invasive cervical cancers. Conversely, expression of activated Notch1 causes strong growth inhibition of HPV-positive, but not HPV-negative, cervical carcinoma cells, but exerts no such effects on other epithelial tumor cells. Increased Notch1 signaling, but not Notch2, causes a dramatic down-modulation of HPV-driven transcription of the E6/E7 viral genes, through suppression of AP-1 activity by up-regulation of the Fra-1 family member and decreased c-Fos expression. Thus, Notch1 exerts specific protective effects against HPV-induced transformation through suppression of E6/E7 expression, and down-modulation of Notch1 expression is likely to play an important role in late stages of HPV-induced carcinogenesis.
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Claudio
C
Talora
Dennis C
DC
Sgroi
Christopher P
CP
Crum
G Paolo
GP
Dotto
D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005814:Genes, Viral; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins; D027383:Papillomaviridae / Q000235:genetics / Q000472:pathogenicity*; D030361:Papillomavirus Infections / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D014412:Tumor Virus Infections / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000821:virology*
D004268:DNA-Binding Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; D009687:Nuclear Proteins; C497570:RBPJ protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface; D018808:Transcription Factor AP-1; D014157:Transcription Factors