Cytosolic accumulation of HPV16 E7 oligomers supports different transformation routes for the prototypic viral oncoprotein: the amyloid-cancer connection.
E7 is the major transforming activity in human papillomaviruses, a causal agent for cervical cancer. HPV16 E7 is a small protein with a natively unfolded domain for which dozens of specific cellular targets were described, and represents a prototypical oncoprotein among small DNA tumor viruses. The protein can form spherical oligomers with amyloid-like properties and chaperone activity. Conformation specific antibodies locate endogenous oligomeric E7 species in the cytosol of 3 model cell lines, strongly co-localizing with amyloid structures and dimeric E7 localizes to the nucleus. The cytosolic oligomeric E7 appear as the most abundant species in all cell systems tested. We show that nuclear E7 levels are replenished dynamically from the cytosolic pool and do not result from protein synthesis. Our results suggest that long-term events related to de-repression of E7 would cause accumulation of excess E7 into oligomeric species in the cytosol. These, together with the known target promiscuity of E7, may allow interactions with many of the non-pRb dependent targets described. This hypothesis is further supported by the detection of E7 oligomers in the cytosol of cancerous cells from tissue biopsies.
Dantur
Karina
K
Instituto Leloir and Instituto de Investigaciones Bioquímicas Buenos Aires, Conicet, Patricias Argentinas 435, (C1405BWE) Ciudad Autonoma de Buenos Aires, Argentina.
Alonso
Leonardo
L
Castaño
Eduardo
E
Morelli
Laura
L
Centeno-Crowley
Juan Manuel
JM
Vighi
Susana
S
de Prat-Gay
Gonzalo
G
D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology; D018269:Carcinoma, Endometrioid / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D003600:Cytosol / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D027383:Papillomaviridae; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000378:metabolism / Q000473:pathology / Q000821:virology; D014162:Transfection; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology
D000682:Amyloid; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16