# Establishing the role of cytoplasmic Core Binding Factor beta in the regulation of osteosarcoma protein translation

> **NIH NIH R03** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $111,350

## Abstract

Project Summary/Abstract
 Osteosarcoma (OS) is the most common primary bone neoplasms in people, with the majority of cases
affecting adolescents and young adults. Up to 30% of those diagnosed will not survive 5 years with current,
multimodal therapy which includes surgery, chemotherapy and, in some cases, radiation therapy. No meaningful
improvements in survival times have been made in the past 40 years, illustrating the desperate need for novel
forms of therapy.
 The core binding factor beta (CBFβ) protein is one subunit of a heterodimeric transcription factor complex
that binds to Runt-related transcription factor 2 (RUNX2) to coordinate organized skeletal development. Both
components are overexpressed in OS and their normal activity is dysregulated. With no inherent DNA binding
nor transcriptional activity of its own, very little is known about the activity of cytoplasmic CBFβ. Yet, this protein
is upregulated in OS, demonstrates increased expression in metastatic lesions, and is associated with reduced
disease free and overall survival. CBFβ appears to control RUNX2 expression through post-transcriptional
mechanisms independent of RUNX2 protein stability or proteasomal degredation. Recently, CBFβ has been
implicated in regulating the initiation of protein translation in breast cancer cells. This project aims to identify and
describe a noncanonical, regulatory role of CBFβ in initiating cap-dependent protein translation in OS, a process
to which malignant cells are thought to be addicted. The goals of this project will be accomplished through the
use of a CBFβ knockout cells transfected with either wild-type CBFβ or asite-directed mutant of CBFβ that targets
the binding site with RUNX2. An inhibitory peptide will be used in additional OS cell lines and normal osteoblast
cells. The Specific Aims of this project will 1) determine the mechanism of post-transcriptional control of RUNX2
protein expression by CBFβ and 2) Identify the contribution of CBFβ to cap-dependent protein translation in
osteosarcoma.
 De novo protein synthesis assays, investigation of CBFβ interactions with translational machinery
proteins, and the ability CBFβ to influence RNA-binding and cap-binding protein interactions with RUNX2 mRNA
will be used to uncover potential mechanisms by which CBFβ exerts post-transcriptional control of RUNX2.
Ribosome footprinting, or Ribo-seq, combined with RNA-seq will identify the role of CBFβ on translational
efficiency of RUNX2 and RUNX2-target gene products. Ribo-seq data will also provide a global view of the
influence of CBFβ on protein translation, and subsequent pathway analysis will provide information about
potential novel targets in OS.
 These studies, when combined with those of the current K01 SERCA, will advance research
independence of the applicant and will be used to develop and refine research hypotheses for inclusion in a
future R01 application.

## Key facts

- **NIH application ID:** 10570684
- **Project number:** 1R03OD031958-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Luke A. Wittenburg
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $111,350
- **Award type:** 1
- **Project period:** 2022-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10570684

## Citation

> US National Institutes of Health, RePORTER application 10570684, Establishing the role of cytoplasmic Core Binding Factor beta in the regulation of osteosarcoma protein translation (1R03OD031958-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10570684. Licensed CC0.

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