Microtubule associated tumor suppressor 1 deficient mice develop spontaneous heart hypertrophy and SLE-like lymphoproliferative disease

Abstract

The microtubule associated tumor suppressor gene 1 (MTUS1) is a recently published tumor suppressor gene, which has also been shown to act as an early component in the growth inhibitory signaling cascade of the angiotensin II type 2 receptor (AT2R). In this study we report the generation of MTUS1 knock-out (KO) mice, which develop normally but reveal higher body weights and slightly decreased blood pressure levels. Twenty-eight percent of the studied MTUS1 KO mice also developed heart hypertrophy and 12% developed nephritis, independent of blood pressure levels. Forty-three percent of the MTUS1 KO mice revealed lymphoid hyperplasia affecting spleen (20%), kidney (37%), lung (23%), lymph nodes (17%), and liver (17%) accompanied with leukocytosis, lymphocytosis, and mild anemia. One animal (3%) developed a marginal zone B-cell lymphoma affecting submandibular salivary gland and regional lymph nodes. The symptoms of all mentioned animals are consistent with a B-cell lymphoproliferative disease with features of systemic lupus erythematosus. In addition, body weight of the MTUS1 KO mice was significantly increased and isolated skin fibroblasts showed increased cell proliferation and decreased cell size, compared to wild-type (WT) fibroblasts in response to depleted FCS concentration and lack of growth factors. In conclusion we herein report the first generation of a MTUS1 KO mouse, developing spontaneous heart hypertrophy and increased cell proliferation, confirming once more the anti-proliferative effect of MTUS1, and a SLE-like lymphoproliferative disease suggesting crucial role in regulation of inflammation. These MTUS1 KO mice can therefore serve as a model for further investigations in cardiovascular disease, autoimmune disease and carcinogenesis.

Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy

“…Recently, Zuern et al revealed that systemic Mtus1 knockout mice, lacking all splice variants, exhibited renal disease, lymphoid hyperplasia, and cardiac hypertrophy. 35 This cardiac phenotype agreed with the present observation; however, because renal diseases are usually associated with cardiac hypertrophy, it is still unclear whether Mtus1 ablation is directly related to cardiac hypertrophy. Moreover, the authors did not clarify which variants affected those phenotypes.…”

Microtubule associated tumor suppressor 1 interacts with mitofusins to regulate mitochondrial morphology in endothelial cells

“…MTUS1 deficiency is implicated in multiple types of cancers. It reportedly plays important roles in vascular remodeling (12), adipocyte differentiation (13), lymphocytosis, and cardiac hypertrophy (14,15). We recently reported that MTUS1 transcript variant 5 is the most abundant isoform in ECs, and the loss of MTUS1 resulted in cAMP response element-binding protein (CREB) binding protein (CREBBP)-mediated NF-kB activation in ECs (16).…”

Cardiovascular ATIP (Angiotensin receptor type 2 interacting protein) expression in mouse development

“…Therefore, we examined in this study the expression of ATIPs during mouse development. To determine the histological location of Mtus1 expression during mouse development, beta‐galactosidase stainings of a gene‐trapped Mtus1 mouse line (Zuern et al, ) were performed (Figs. ).…”

“…Since Mtus1 is abundantly expressed during cardiovascular development, we would expect severe cardiac malformations and early lethality in Mtus1 knockout mice. However, this is not the case (Zuern et al, ), suggesting that other factors are compensating for the loss of ATIP. One predestinated candidate for this is the Mtus2 gene product CAZIP (also designated TIP150 or KIAA0774 in chicken).…”

“…Thereby, it provides a very sensitive and cell‐specific method to illustrate the endogenous promoter activity, whereas the X‐Gal intensity is considered as proportional to the beta‐galactosidase expression level. In this study, we describe the spacial and temporal promoter activity pattern of the Mtus1 gene during embryonic mouse development from day E7.5 to E12.5 by using a gene‐trapped Lac‐Z reporter that was placed under control of the endogenous Mtus1 gene promoter (Zuern et al, ), and we confirmed these data by investigating mRNA and protein expression profiles.…”