Non-canonical roles for the E2F family in the survival and proliferation of stem and cancer cells
Abstract/Contents
- Abstract
- The E2F family of transcription factors has a well-known, critical role in cell cycle regulation. At the G1/S checkpoint, the canonical "repressor" E2Fs inhibit the expression of cell cycle genes in conjunction with the RB family proteins, while the canonical "activator" E2Fs activate the expression of cell cycle genes in response to mitogenic cues. However, accumulating evidence points toward diverse functions for the E2F family outside of G1/S checkpoint regulation. For instance, loss-of-function studies suggest that specific E2F family members are required for cellular differentiation, self-renewal, and apoptosis in a context-dependent manner. In addition, the "repressor" and "activator" designations are based on in vitro studies in a few cell types, and the E2Fs may also have different molecular functions in physiological conditions, including in the cytoplasm. These non-canonical roles remain largely unexplored. Our work shows that E2F4, a canonical "repressor" E2F, can switch to an activator of cell cycle genes to promote the survival and proliferation of embryonic stem cells (ES cells). We demonstrate that E2F4 loss leads to cell cycle defects at the G1 and S phases, decreased cell viability, and global downregulation of cell cycle genes, and that rescue of E2F4 function relies on both its DNA binding and transactivation domains. We further demonstrate that the function of E2F4 in ES cells is RB family-independent, as E2F4 can translocate into the nucleus and bind to gene promoters in cells that completely lack RB family activity. Finally, we characterized the interactomes of E2F4 in ES cells and somatic cells, and found ES cell-specific interactors (e.g. components of the MLL methyltransferase complex) that may be critical for the activator function of E2F4. Our data reveal a non-canonical function for a well-known repressor E2F, and may lead to insights into the biology of other rapidly cycling cell types (e.g. cancer cells and progenitor cells) that lack RB family activity. Future work will be needed to examine the mechanisms driving gene activation by E2F4, the different protein complexes to which E2F4 contributes, and the plethora of cellular functions controlled by the E2F family members.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2018; ©2018 |
| Publication date | 2018; 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Hsu, Jenny |
|---|---|
| Degree supervisor | Sage, Julien |
| Thesis advisor | Sage, Julien |
| Thesis advisor | Attardi, Laura |
| Thesis advisor | Kundaje, Anshul, 1980- |
| Thesis advisor | Lipsick, Joseph Steven, 1955- |
| Degree committee member | Attardi, Laura |
| Degree committee member | Kundaje, Anshul, 1980- |
| Degree committee member | Lipsick, Joseph Steven, 1955- |
| Associated with | Stanford University, Department of Genetics. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Jenny Hsu. |
|---|---|
| Note | Submitted to the Department of Genetics. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Jenny Hsu
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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