Multiple interference of the human papillomavirus-16 E7 oncoprotein with the functional role of the metastasis suppressor Nm23-H1 protein.
High-risk human papillomaviruses (HPV) are linked to human cervical and other ano-genital cancers. Integration of the viral genome in the transformed epithelial cells is restricted to the coding regions for the E6 and E7 oncoproteins. Nevertheless, E7 plays the major role in cell transformation. We report a novel interaction between HPV-16 E7 and the Nm23-H1 and Nm23-H2 proteins identified in yeast by the two-hybrid system and confirmed by co-immunoprecipitation in the human keratinocyte HaCaT cell line. Expression of the E7 oncoprotein in HaCaT cells induces modified keratinocyte proliferation and differentiation patterns, and leads to down-modulation and functional inactivation of the metastasis suppressor Nm23-H1 protein. Both transcriptional down-regulation and protein degradation contribute to reduce Nm23-H1 intracellular content. Besides metastasis suppression, Nm23-H1 displays multiple functions in cell cycle regulation and differentiation, development, DNA regulation and caspase-independent apoptosis. As a consequence of Nm23-H1 inhibition, HPV-16 E7 expressing HaCaT cells, acquire invasiveness capabilities and resistance to granzyme A-induced apoptosis. We propose that impairment of the multifunctional role of Nm23-H1 is an important feature consistent with the complex strategy carried out by HPV-16 E7 to promote cell transformation and tumor progression.
Mileo
Anna Maria
AM
Department for the Development of Therapeutic Programs, Laboratory C, Regina Elena Cancer Institute, Centre for Experimental Research, Via delle Messi d'Oro 156, 00158, Rome, Italy.
Piombino
Emanuela
E
Severino
Anna
A
Tritarelli
Alessandra
A
Paggi
Marco G
MG
Lombardi
Daniela
D
D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005982:Glutathione Transferase; D052162:Human papillomavirus 16 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D015603:Keratinocytes / Q000378:metabolism; D054778:NM23 Nucleoside Diphosphate Kinases; D009369:Neoplasms / Q000378:metabolism / Q000821:virology*; D009701:Nucleoside-Diphosphate Kinase / Q000235:genetics / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D016662:Virus Integration / Q000235:genetics / Q000502:physiology*; D015003:Yeasts
D054778:NM23 Nucleoside Diphosphate Kinases; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D005982:Glutathione Transferase; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase