Haploinsufficiency of the Myc regulator Mtbp extends survival and delays tumor development in aging mice.

Alterations of specific genes can modulate aging. Myc, a transcription factor that regulates the expression of many genes involved in critical cellular functions was shown to have a role in controlling longevity. Decreased expression of Myc inhibited many of the deleterious effects of aging and increased lifespan in mice. Without altering Myc expression, reduced levels of Mtbp, a recently identified regulator of Myc, limit Myc transcriptional activity and proliferation, while increased levels promote Myc-mediated effects. To determine the contribution of Mtbp to the effects of Myc on aging, we studied a large cohort of Mtbp heterozygous mice and littermate matched wild-type controls. Mtbp haploinsufficiency significantly increased longevity and maximal survival in mice. Reduced levels of Mtbp did not alter locomotor activity, litter size, or body size, but Mtbp heterozygous mice did exhibit elevated markers of metabolism, particularly in the liver. Mtbp(+/-) mice also had a significant delay in spontaneous cancer development, which was most prominent in the hematopoietic system, and an altered tumor spectrum compared to Mtbp(+/+) mice. Therefore, the data suggest Mtbp is a regulator of longevity in mice that mimics some, but not all, of the properties of Myc in aging

MTBP and MYC: A Dynamic Duo in Proliferation, Cancer, and Aging

The oncogenic transcription factor c-MYC (MYC) is highly conserved across species and is frequently overexpressed or dysregulated in human cancers. MYC regulates a wide range of critical cellular and oncogenic activities including proliferation, metabolism, metastasis, apoptosis, and differentiation by transcriptionally activating or repressing the expression of a large number of genes. This activity of MYC is not carried out in isolation, instead relying on its association with a myriad of protein cofactors. We determined that MDM Two Binding Protein (MTBP) indirectly binds MYC and is a novel MYC transcriptional cofactor. MTBP promotes MYC-mediated transcriptional activity, proliferation, and cellular transformation by binding in a protein complex with MYC at MYC-bound promoters. This discovery provided critical context for data linking MTBP to aging as well as a rapidly expanding body of evidence demonstrating MTBP is overexpressed in many human malignancies, is often linked to poor patient outcomes, and is necessary for cancer cell survival. As such, MTBP represents a novel and potentially broad reaching oncologic drug target, particularly when MYC is dysregulated. Here we have reviewed the discovery of MTBP and the initial controversy with its function as well as its associations with proliferation, MYC, DNA replication, aging, and human cancer

MTBP Is Overexpressed in Triple-Negative Breast Cancer and Contributes to Its Growth and Survival

Triple negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer commonly resistant to therapeutics that have been successful in increasing survival in ER+ and HER2+ breast cancer patients. As such, identifying factors that contribute to poor patient outcomes and mediate the growth and survival of TNBC cells remain important areas of investigation. MTBP (MDM2 Binding Protein), a gene linked to cellular proliferation and a transcriptional target of the MYC oncogene, is over-expressed in human malignancies, yet its contribution to cancer remains unresolved. Evaluation of mRNA expression and copy number variation data from The Cancer Genome Atlas (TCGA) revealed MTBP is commonly over-expressed in breast cancer and 19% show amplification of MTBP. Increased transcript or gene amplification of MTBP significantly correlated with reduced breast cancer patient survival. Further analysis revealed that while MTBP mRNA is over-expressed in both ER+ and HER2+ breast cancers, its expression is highest in TNBC. MTBP mRNA and protein levels were also significantly elevated in a panel of human TNBC cell lines. Knockdown of MTBP in TNBC model systems induced apoptosis and significantly reduced TNBC cell growth and soft agar colony formation, which was rescued by expression of shRNA-resistant Mtbp. Notably, inducible knockdown of MTBP expression significantly impaired TNBC tumor growth, in vivo, including in established tumors. Thus, these data emphasize MTBP is important for the growth and survival of TNBC and warrants further investigation as a potential novel therapeutic target. Implications: MTBP significantly contributes to breast cancer survival and is a potential novel therapeutic target in TNBC

Oncogenic Protein MTBP Interacts with MYC to Promote Tumorigenesis

Despite its involvement in most human cancers, MYC continues to pose a challenge as a readily tractable therapeutic target. Here we identify the MYC transcriptional cofactors TIP48 and TIP49 and MYC as novel binding partners of MTBP, a functionally undefined protein that we show is oncogenic and overexpressed in many human cancers. MTBP associated with MYC at promoters and increased MYC-mediated transcription, proliferation, neoplastic transformation and tumor development. In breast cancer specimens, we determined overexpression of both MYC and MTBP was associated with a reduction in 10-year patient survival compared to MYC overexpression alone. MTBP was also frequently co-amplified with MYC in many human cancers. Mechanistic investigations implicated associations with TIP48/TIP49 as well as MYC in MTBP function in cellular transformation and the growth of human breast cancer cells. Taken together, our findings show MTBP functions with MYC to promote malignancy, identifying this protein as a novel general therapeutic target in human cancer