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Disruption of retinoblastoma protein family function by human papillomavirus type 16 E7 oncoprotein inhibits lens
J McCaffrey1, L Yamasaki, N J Dyson
1Department of Anatomy, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA.
Abstract:
Complexes between the retinoblastoma protein (pRb) and the transcription factor E2F-1 are thought to be important for regulating cell proliferation. We have shown previously that the E7 oncoprotein from human papillomavirus type 16, dependent upon its binding to pRb proteins, induces proliferation, disrupts differentiation, and induces apoptosis when expressed in the differentiating, or fiber, cells of the ocular lenses in transgenic mice. Mice that carry a null mutation in E2F-1 do not exhibit any defects in proliferation and differentiation in the lens. By examining the lens phenotype in mice that express E7 on an E2F-1 null background, we now show genetic evidence that E7's ability to alter the fate of fiber cells is partially dependent on E2F-1. On the other hand, E2F-1 status does not affect E7-induced proliferation in the undifferentiated lens epithelium. These data provide genetic evidence that E2F-1, while dispensible for normal fiber cell differentiation, is one mediator of E7's activity in vivo and that the requirement for E2F-1 is context dependent. These data suggest that an important role for pRb-E2F-1 complex during fiber cell differentiation is to negatively regulate cell cycle progression, thereby allowing completion of the differentiation program to occur.
Insights
Human papillomavirus type 16 E7 oncoprotein alters ocular lens fiber cell fate, partly requiring the transcription factor E2F-1. This highlights E2F-1
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- The retinoblastoma protein (pRb) and transcription factor E2F-1 complex regulates cell proliferation.
- The human papillomavirus type 16 E7 oncoprotein targets pRb, affecting cell behavior.
Purpose of the Study:
- To investigate the role of E2F-1 in mediating the effects of the E7 oncoprotein in ocular lens fiber cells.
- To determine if E7-induced proliferation and differentiation disruption in the ocular lens is dependent on E2F-1.
Main Methods:
- Utilized transgenic mice expressing the E7 oncoprotein on an E2F-1 null background.
- Examined the ocular lens phenotype, focusing on fiber cell differentiation and proliferation.
- Assessed E7-induced proliferation in undifferentiated lens epithelium.
Main Results:
- E7's disruption of ocular lens fiber cell differentiation is partially dependent on E2F-1.
- E2F-1 status did not influence E7-induced proliferation in undifferentiated lens epithelium.
- E2F-1 is a context-dependent mediator of E7 activity in vivo.
Conclusions:
- E2F-1 plays a role in mediating the effects of the E7 oncoprotein on ocular lens fiber cell fate.
- The pRb-E2F-1 complex negatively regulates cell cycle progression during fiber cell differentiation.
- E2F-1 is essential for normal fiber cell differentiation but dispensable for E7-induced proliferation in the lens epithelium.