American Association for Cancer Research
Browse

Supplementary Figure from PARK2 Regulates eIF4B-Driven Lymphomagenesis

Download (8.7 MB)
journal contribution
posted on 2023-04-03, 20:03 authored by Bandish B. Kapadia, Anirban Roychowdhury, Forum Kayastha, Nahid Nanaji, Ronald B. Gartenhaus
Supplementary Figure from PARK2 Regulates eIF4B-Driven Lymphomagenesis

Funding

Merit Review Award from the Department of Veterans Affairs

Massey NIH

NCI

History

ARTICLE ABSTRACT

Patients with high-risk diffuse large B-cell lymphoma have poor outcomes following first-line cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP); thus, treatment of this fatal disease remains an area of unmet medical need and requires identification of novel therapeutic approaches. Dysregulation of protein translation initiation has emerged as a common downstream node in several malignancies, including lymphoma. Ubiquitination, a prominent posttranslational modification associated with substrate degradation, has recently been shown to be a key modulator of nascent peptide synthesis by limiting several translational initiation factors. While a few deubiquitinases have been identified, the E3 ligase responsible for the critical ubiquitination of these translational initiation factors is still unknown. In this study, using complementary cellular models along with clinical readouts, we establish that PARK2 ubiquitinates eIF4B and consequently regulates overall protein translational activity. The formation of this interaction depends on upstream signaling, which is negatively regulated at the protein level of PARK2. Through biochemical, mutational, and genetic studies, we identified PARK2 as a mTORC1 substrate. mTORC1 phosphorylates PARK2 at Ser127, which blocks its cellular ubiquitination activity, thereby hindering its tumor suppressor effect on eIF4B's stability. This resultant increase of eIF4B protein level helps drive enhanced overall protein translation. These data support a novel paradigm in which PARK2-generated eIF4B ubiquitination serves as an anti-oncogenic intracellular inhibitor of protein translation, attenuated by mTORC1 signaling. Our data implicate the FASN/mTOR-PARK2-eIF4B axis as a critical driver of enhanced oncogene expression contributing to lymphomagenesis.

Usage metrics

    Molecular Cancer Research

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC