# Regulation of the cell cycle and growth signaling pathways by a sensing mechanism for Vitamin B5-Coenzyme A metabolism

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2021 · $33,799

## Abstract

Abstract
 The cellular decision to grow and divide relies on sensing mechanisms for growth factors and nutrients.
Multiple cellular sensing pathways converge at the central signaling node of the mechanistic target of
rapamycin complex 1 (mTORC1), a master regulator of metabolism. While amino acid and glucose deprivation
are known to inactivate mTORC1 through well-defined mechanisms, it remains unknown whether sensing
mechanisms exist for vitamins and cofactors, which are equally important for central carbon metabolism. Here,
abundance of the essential nutrient Vitamin B5 (VB5) was shown to influence cell cycle progression and
mTORC1 activation. VB5 is the precursor for Coenzyme A (CoA), an acyl chain carrier necessary for central
carbon metabolism. However, response to perturbation of VB5/CoA metabolism is not due to cellular energy
depletion, suggesting that the phenotype does not simply reflect decreased carbon source oxidation. While
non-transformed cells undergo stable cell cycle arrest under selective VB5 depletion, cell lines lacking tumor
suppressors involved in regulation of the cell cycle and mTORC1 instead undergo cell death. Therefore, cell
cycle arrest and mTORC1 inhibition appear to be necessary for survival of perturbed VB5/CoA metabolism. If
VB5 is sensed through a downstream metabolite, then patients with cancer cells lacking specific tumor
suppressors, or tuberous sclerosis complex patients in which mTORC1 is dysregulated, could be potentially
targeted with inhibitors of CoA synthesis. The proposed aims are designed to 1) identify the cell cycle
regulatory machinery necessary for survival in VB5 depletion and 2) determine the molecular mechanism of
VB5-mediated mTORC1 regulation by investigating the roles of mTORC1-regulating protein complexes and
metabolites. Both aims will characterize sensitivity to inhibition of CoA synthesis in cells lacking the tumor
suppressors involved in each pathway. These research questions will be addressed by genetic ablation of key
cell cycle and mTORC1 regulators and perturbation of VB5/CoA metabolism through selective VB5 depletion
and pharmacological inhibition of CoA synthesis. Biochemical and mass spectrometry techniques will be used
to investigate the influence of VB5/CoA abundance on signaling proteins and metabolites. The proposed work
will shed light on a novel vitamin-sensing mechanism and define its regulation of critical cellular growth and
proliferative pathways, with the potential to reveal targetable cancer cell metabolic vulnerabilities.

## Key facts

- **NIH application ID:** 10236292
- **Project number:** 5F31CA254169-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Samuel Barritt
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,799
- **Award type:** 5
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236292

## Citation

> US National Institutes of Health, RePORTER application 10236292, Regulation of the cell cycle and growth signaling pathways by a sensing mechanism for Vitamin B5-Coenzyme A metabolism (5F31CA254169-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10236292. Licensed CC0.

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