Summary of project PR001262
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001262. The data can be accessed directly via it's Project DOI: 10.21228/M8KM58 This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR001262 |
| Project DOI: | doi: 10.21228/M8KM58 |
| Project Title: | Fbxo7 promotes Cdk6 activity to inhibit PFKP and glycolysis in T cells |
| Project Type: | T cell biology |
| Project Summary: | Deregulated Fbxo7 expression is associated with many pathologies, including anaemia, male sterility, cancer, and Parkinson’s disease, demonstrating its critical role in a variety of cell types. Although Fbxo7 is an F-box protein that recruits substrates for SCF-type E3 ubiquitin ligases, it also promotes the formation of cyclin D/Cdk6/p27 complexes in an E3-ligase independent fashion. We discovered PFKP, the major gatekeeper of glycolysis, in a screen for Fbxo7 substrates. PFKP has been previously shown to be a critical substrate of Cdk6 for the viability of T-ALL cells experiencing high levels of reactive oxygen species. We investigated the molecular relationships between Fbxo7, Cdk6 and PFKP, and the functional effect Fbxo7 has on T cell metabolism, viability, and activation. Fbxo7 promotes Cdk6-independent ubiquitination and Cdk6-dependent phosphorylation of PFKP. Importantly Fbxo7-deficient cells have reduced Cdk6 activity, and haematopoietic and lymphocytic cell lines show a significant dependency on Fbxo7. CD4+ T cells with reduced Fbxo7 have increased glycolysis, and lower cell viability and activation levels. Metabolomic studies of activated CD4+ T cells confirm increased glycolytic flux in Fbxo7-deficient cells, as well as altered nucleotide biosynthesis and arginine metabolism. We show Fbxo7 expression is glucose-responsive, and we propose Fbxo7 inhibits PFKP and glycolysis via its activation of Cdk6. |
| Institute: | University of Cambridge |
| Department: | Department of Pathology |
| Laboratory: | Laman Lab |
| Last Name: | Heike |
| First Name: | Laman |
| Address: | Tennis Court Road, Cambridge CB2 1QP, UK |
| Email: | hl316@cam.ac.uk |
| Phone: | +44 (0)1223 333722 |
| Contributors: | Rebecca Harris, Ming Yang, Christina Schmidt, Sarbjit Singh, Amarnath Natarajan, Christian Frezza, and Heike Laman |
Summary of all studies in project PR001262
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST001986 | Fbxo7 promotes Cdk6 activity to inhibit PFKP and glycolysis in T cells | Mus musculus | University of Cambridge | MS | 2022-11-16 | 1 | 12 | Uploaded data (1.2G)* |
