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

Abstract

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.

Genomic expansion of Aldh1a1 protects beavers against high metabolic aldehydes from lipid oxidation

“…Different alleles of Hsd17b1 were found to be significantly associated with human longevity in females ( Scarabino et al, 2015 ). A single knockout of Mtbp in mice led to an extension of lifespan ( Grieb et al, 2016 ). Knockdown of Mrpl37 increased the lifespan of Caenorhabditis elegans by 41% on average ( Houtkooper et al, 2013 ).…”

“…We examined a few other sequence changes at the positive selection sites in other mammals and found that only changes in beaver Mtbp were predicted to be deleterious ( Figure S11D ), which may contribute to its cancer resistance. Haploinsufficiency of Mtbp in mice delays spontaneous cancer development and extends lifespan by enhancing Tp53 function ( Grieb et al, 2016 ). Our hypothesis on the decreased function of Mtbp, due to deleterious mutations, is supported by the lower expression of Mtbp in beavers than in mice ( Figure 4C ).…”

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

“…Nevertheless, increased MTBP expression is also able to promote neurosphere formation [ 19 ]. Additionally, compared to wild-type littermates, Mtbp heterozygous mice had reduced spontaneous cancer development [ 11 ]. Taken together, the data indicate that MTBP has oncogenic activity.…”

“…Consistent with its oncogenic role, MTBP has been shown to be overexpressed in a wide range of human cancers, where it is associated with poor patient outcomes in the majority of malignant contexts [ 4 , 8 , 9 , 10 ]. Moreover, suppression of MTBP expression in malignant cells or expression of a mutant with apparent dominant-negative activity demonstrated MTBP-directed therapeutics could have broad applicability as cancer therapies and extending patient survival [ 3 , 4 , 8 , 11 ], similar to its binding partner MYC. Herein, we review these advances and raise lingering questions.…”

Investigating Reptin function in Acute Myeloid Leukaemia

“…MTBP is an oncogenic protein that was found to be overexpressed in different human cancers and to promote c-MYC driven transformation in conjunction with Reptin and Pontin (Grieb et al, 2014). Moreover, mice expressing reduced levels of MTBP or c-MYC were found to have a significant delay in spontaneous cancer development, particularly prominent in the haematopoietic compartment (Grieb et al, 2016).…”