Molecular analysis of the role of E2F proteins in the pRB pathway
Author(s)Moberg, Kenneth H. (Kenneth Harold), 1967-
Jacqueline A. Lees.
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The E2F family of transcription factors appear to represent the primary cellular target of the tumor suppressive properties of the retinoblastoma protein. E2F therefore functions in a pathway which is a frequent target in human cancer, and the tumorigenicity of these mutations may be mediated at the transcriptional level by E2F. E2F is also regulated by cell cycle-dependent interactions with the pRB-related proteins p107 and p130. Unlike pRB, mutations in p107 or p130 are not associated with cancer. The different properties of the pRB family may result from the manner in which each protein regulates E2F. To determine how individual E2Fs contribute to the cell cycle regulatory properties of pRB, p107 and p1 30, we have examined the regulation of individual members of the E2F family. Our data suggest that the induction of E2F responsive genes is primarily due to the loss of nuclear repressor complexes at G1/S. This loss correlates with the disappearance of nuclear forms of E2F-4 protein, which represents the majority of pRBbound nuclear E2F during G1. These data suggests that E2F-4, the most abundant E2F in vivo, acts primarily as the DNA-binding component of a G1 transcriptional repressor complex. In contrast, we find that E2F-1, -2 and -3 are present at low levels in vivo and localize to the nucleus by virtue of a nuclear localization signal sequence in the N-terminal domain of these proteins. Their constitutive nuclear localization suggests that these E2F family members will contribute to the activation of responsive gene transcription during S-phase. Together, these data suggest that induction of E2F-responsive genes at G1/S is triggered both by the loss of an abundant transcriptional repressor, E2F-4*pRB, and by the presence of nuclear forms of E2F capable of transcriptional activation. These functional differences among E2Fs may underlie the oncogenic consequences specifically associated with pRB loss. Inactivation of pRB is predicted to both abrogate repression of E2F-responsive genes, and relieve inhibition of nuclear, activatory E2Fs. The combined effect of these forms of transcriptional deregulation of the E2F pathway may be sufficient to promote transformation in vivo.
Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Biology, 1998.Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Dept. of Biology
Massachusetts Institute of Technology