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PMID:23729654

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Citation

Mileo, AM, Abbruzzese, C, Vico, C, Bellacchio, E, Matarrese, P, Ascione, B, Federico, A, Della Bianca, S, Mattarocci, S, Malorni, W and Paggi, MG (2013) The human papillomavirus-16 E7 oncoprotein exerts antiapoptotic effects via its physical interaction with the actin-binding protein gelsolin. Carcinogenesis 34:2424-33

Abstract

The oncoprotein E7 from human papillomavirus-16 (HPV-16 E7) plays a pivotal role in HPV postinfective carcinogenesis, and its physical interaction with host cell targets is essential to its activity. We identified a novel cellular partner for the viral oncoprotein: the actin-binding protein gelsolin (GSN), a key regulator of actin filament assembly and disassembly. In fact, biochemical analyses, generation of a 3D molecular interaction model and the use of specific HPV-16 E7 mutants provided clear cut evidence supporting the crucial role of HPV-16 E7 in affecting GSN integrity and function in human immortalized keratinocytes. Accordingly, functional analyses clearly suggested that stable HPV-16 E7 expression induced an imbalance between polymeric and monomeric actin in favor of the former. These events also lead to changes of cell cycle (increased S phase), to the inhibition of apoptosis and to the increase of cell survival. These results provide support to the hypotheses generated from the 3D molecular interaction model and encourage the design of small molecules hindering HPV-induced host cell reprogramming by specifically targeting HPV-16 E7-expressing cells.

Links

PubMed Online version:10.1093/carcin/bgt192

Keywords

Actins/metabolism; Amino Acid Motifs; Amino Acid Sequence; Apoptosis; Caspase 3/metabolism; Cell Line, Tumor; Gelsolin/chemistry; Gelsolin/metabolism; Humans; Molecular Docking Simulation; Mutation; Papillomavirus E7 Proteins/chemistry; Papillomavirus E7 Proteins/genetics; Papillomavirus E7 Proteins/metabolism; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs; Protein Interaction Mapping

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HPV16:VE7

involved_in

GO:0030838: positive regulation of actin filament polymerization

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P06396)

Seeded From UniProt

complete

HPV16:VE7

involved_in

GO:0039650: suppression by virus of host cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P42574)
  • has_input:(UniProtKB:P06396)

Seeded From UniProt

complete

HUMAN:CASP3

enables

GO:0097153: cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:P06396)

Seeded From UniProt

complete

HPV16:VE7

colocalizes_with

GO:0042025: host cell nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HPV16:VE7

involved_in

GO:0039650: suppression by virus of host cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_regulation_target:(UniProtKB:P42574)
  • has_input:(UniProtKB:P06396)

Seeded From UniProt

complete

HPV16:VE7

involved_in

GO:0030838: positive regulation of actin filament polymerization

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(UniProtKB:P06396)

Seeded From UniProt

complete

HUMAN:GELS

involved_in

GO:0030041: actin filament polymerization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GELS

involved_in

GO:1902174: positive regulation of keratinocyte apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GELS

colocalizes_with

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CASP3

enables

GO:0097153: cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

F

has_direct_input:(UniProtKB:P06396)

Seeded From UniProt

complete

Notes

See also

References

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