Cell cycle exit in G1 and differentiation independent of the Retinoblastoma gene family during development
Abstract/Contents
- Abstract
- The ability of stem/progenitor cells to exit the cell cycle is essential for proper embryonic development, but the mechanisms governing cell cycle exit are still not fully understood. Correct regulation of G1 is critical for ensuring proper organismal development, tissue homeostasis, and tumor suppression. The Retinoblastoma (Rb) gene family is composed of three genes, Rb, p107, and p130, which are collectively thought to serve as essential regulators of the G1 phase of the cell cycle in most proliferating cell types. The Rb family has also been implicated in promoting the gene expression of several differentiation programs in different cell lineages. However, due to the overlapping and compensatory functions among the Rb family members, a complete understanding of how the Rb family controls the cell cycle and differentiation programs within a cell remains unclear. Furthermore, it has not yet been tested whether the Rb family members are the only mediators of these cellular processes, or if there are alternative mechanisms for cell cycle exit and differentiation in mammalian stem and progenitor cells. Here we tested the requirement for the Rb protein and its family members p107 and p130 in G1 arrest and differentiation in mammalian cells. We employed several strategies to conditionally remove the Rb family genes in entire embryos and in specific neural lineages, as well as multiple differentiation systems in vitro. We found that Rb family triple knock-out (TKO) mouse embryos survive until days 9-11 of gestation, with similar patterning and organogenesis as seen in wild type embryos. Strikingly, a number of TKO cells, including in the neural lineage, are able to exit the cell cycle in G1 and fully differentiate in vivo and in culture. This ability of TKO cells to arrest in G1 is associated with the repression of key cell cycle target genes for E2F and Myc transcription factors. Thus, G1 arrest can be achieved independently of Rb family members, illustrating the robustness of cell cycle regulatory networks during embryogenesis, and identifying a novel program that regulates cell cycle exit in G1 in mammalian cells.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2010 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Wirt, Stacey Ellen |
|---|---|
| Associated with | Stanford University, Department of Cancer Biology. |
| Primary advisor | Sage, Julien |
| Thesis advisor | Sage, Julien |
| Thesis advisor | Artandi, Steven E |
| Thesis advisor | McConnell, Susan K |
| Thesis advisor | Wong, Albert J |
| Advisor | Artandi, Steven E |
| Advisor | McConnell, Susan K |
| Advisor | Wong, Albert J |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Stacey Ellen Wirt. |
|---|---|
| Note | Submitted to the Department of Cancer Biology. |
| Thesis | Ph.D. Stanford University 2010 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2010 by Stacey Ellen Wirt
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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