Metabolic regulation of mammalian cell growth and proliferation
Proliferation requires that cells acquire sufficient biomass to produce two daughter cells. To accomplish this, cells must utilize available nutrients to generate new components of cell mass, including proteins, lipids, and nucleic acids. In addition, cells must coordinate biosynthesis and productio...
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| Format: | Thesis |
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Massachusetts Institute of Technology
2022
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| Online Access: | https://hdl.handle.net/1721.1/142699 |
| _version_ | 1811085112457035776 |
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| author | Diehl, Frances Flewelling |
| author2 | Vander Heiden, Matthew G. |
| author_facet | Vander Heiden, Matthew G. Diehl, Frances Flewelling |
| author_sort | Diehl, Frances Flewelling |
| collection | MIT |
| description | Proliferation requires that cells acquire sufficient biomass to produce two daughter cells. To accomplish this, cells must utilize available nutrients to generate new components of cell mass, including proteins, lipids, and nucleic acids. In addition, cells must coordinate biosynthesis and production of specific macromolecules with the events that enable cell cycle progression. A cell’s ability to fulfill these anabolic requirements is impacted by environmental factors that influence how the metabolic network is used. This dissertation examines how cells regulate their biosynthesis to enable coordinated growth and division, and how metabolic dependencies impact proliferation. We first investigated why cells that genetically upregulate serine synthesis still rely on consuming large amounts of serine from the environment. We found that serine synthesis is constrained by availability of the oxidizing cofactor NAD+, and that decreased production of purine nucleotides downstream of serine limits proliferation. These findings demonstrate that regeneration of NAD+ can be a limitation for serine and nucleotide synthesis that constrains proliferation. We next determined how cells respond to perturbations to relative levels of nucleotide species. We found that imbalanced nucleotides inhibit cell proliferation, but do not constrain cell growth, allowing cells to grow excessively large. Instead, nucleotide imbalance is not sensed until cells enter S phase, when the replication stress response becomes critical for cell survival. Moreover, we found that replication stress sensing promotes nucleotide availability during normal S phases, suggesting that proliferating cells enter S phase without sensing whether they have sufficient nucleotides. Together, these studies contribute new insights into how metabolism is regulated to support cell growth and division. |
| first_indexed | 2024-09-23T13:03:06Z |
| format | Thesis |
| id | mit-1721.1/142699 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T13:03:06Z |
| publishDate | 2022 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1426992022-05-25T03:21:49Z Metabolic regulation of mammalian cell growth and proliferation Diehl, Frances Flewelling Vander Heiden, Matthew G. Massachusetts Institute of Technology. Department of Biology Proliferation requires that cells acquire sufficient biomass to produce two daughter cells. To accomplish this, cells must utilize available nutrients to generate new components of cell mass, including proteins, lipids, and nucleic acids. In addition, cells must coordinate biosynthesis and production of specific macromolecules with the events that enable cell cycle progression. A cell’s ability to fulfill these anabolic requirements is impacted by environmental factors that influence how the metabolic network is used. This dissertation examines how cells regulate their biosynthesis to enable coordinated growth and division, and how metabolic dependencies impact proliferation. We first investigated why cells that genetically upregulate serine synthesis still rely on consuming large amounts of serine from the environment. We found that serine synthesis is constrained by availability of the oxidizing cofactor NAD+, and that decreased production of purine nucleotides downstream of serine limits proliferation. These findings demonstrate that regeneration of NAD+ can be a limitation for serine and nucleotide synthesis that constrains proliferation. We next determined how cells respond to perturbations to relative levels of nucleotide species. We found that imbalanced nucleotides inhibit cell proliferation, but do not constrain cell growth, allowing cells to grow excessively large. Instead, nucleotide imbalance is not sensed until cells enter S phase, when the replication stress response becomes critical for cell survival. Moreover, we found that replication stress sensing promotes nucleotide availability during normal S phases, suggesting that proliferating cells enter S phase without sensing whether they have sufficient nucleotides. Together, these studies contribute new insights into how metabolism is regulated to support cell growth and division. Ph.D. 2022-05-24T19:19:46Z 2022-05-24T19:19:46Z 2021-09 2022-05-19T17:56:13.029Z Thesis https://hdl.handle.net/1721.1/142699 In Copyright - Educational Use Permitted Copyright retained by author(s) https://rightsstatements.org/page/InC-EDU/1.0/ application/pdf Massachusetts Institute of Technology |
| spellingShingle | Diehl, Frances Flewelling Metabolic regulation of mammalian cell growth and proliferation |
| title | Metabolic regulation of mammalian cell growth and proliferation |
| title_full | Metabolic regulation of mammalian cell growth and proliferation |
| title_fullStr | Metabolic regulation of mammalian cell growth and proliferation |
| title_full_unstemmed | Metabolic regulation of mammalian cell growth and proliferation |
| title_short | Metabolic regulation of mammalian cell growth and proliferation |
| title_sort | metabolic regulation of mammalian cell growth and proliferation |
| url | https://hdl.handle.net/1721.1/142699 |
| work_keys_str_mv | AT diehlfrancesflewelling metabolicregulationofmammaliancellgrowthandproliferation |