SMAD7 enhances adult β-cell proliferation without significantly affecting β-cell function in mice

Abstract

The interplay between the transforming growth factor β (TGF-β) signaling proteins, SMAD family member 2 (SMAD2) and 3 (SMAD3), and the TGF-β–inhibiting SMAD, SMAD7, seems to play a vital role in proper pancreatic endocrine development and also in normal β-cell function in adult pancreatic islets. Here, we generated conditional SMAD7 knockout mice by crossing insulin1Cre mice with SMAD7fx/fx mice. We also created a β cell–specific SMAD7-overexpressing mouse line by crossing insulin1Dre mice with HPRT-SMAD7/RosaGFP mice. We analyzed β-cell function in adult islets when SMAD7 was either absent or overexpressed in β cells. Loss of SMAD7 in β cells inhibited proliferation, and SMAD7 overexpression enhanced cell proliferation. However, alterations in basic glucose homeostasis were not detectable following either SMAD7 deletion or overexpression in β cells. Our results show that both the absence and overexpression of SMAD7 affect TGF-β signaling and modulates β-cell proliferation but does not appear to alter β-cell function. Reversible SMAD7 overexpression may represent an attractive therapeutic option to enhance β-cell proliferation without negative effects on β-cell function.

microRNA‐148a‐3p in extracellular vesicles derived from bone marrow mesenchymal stem cells suppresses SMURF1 to prevent osteonecrosis of femoral head

“…11 Furthermore, down-regulated Smad ubiquitination regulatory factor 1 (SMURF1) is found to promote the expression of SMAD7 in mesangial cells. 12,13 SMAD7 is promoted by the interaction between microtubule actin crosslinking factor 1 and SMAD7 to accelerate the osteogenesis. 14 Furthermore, up-regulated SMAD7 is closely related to the proliferation of BMSCs.…”

“…SMURF1 has the homology with E6AP C‐terminus‐type E3 ubiquitin ligase, thereby being involved in bone morphogenetic protein and remodelling 11 . Furthermore, down‐regulated Smad ubiquitination regulatory factor 1 (SMURF1) is found to promote the expression of SMAD7 in mesangial cells 12,13 . SMAD7 is promoted by the interaction between microtubule actin crosslinking factor 1 and SMAD7 to accelerate the osteogenesis 14 .…”

Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

“…SMAD4/DPC4, a putative tumor suppressor in pancreatic carcinoma, was mutated or deleted in 55% (5 of 9) of non-functioning pNETs but remained intact in 100% of the less aggressive, functional pNETs (insulinomas, gastrinomas, and VIPnomas) [276]. Notably, SMAD7, an inhibitor of SMAD2/3 and thus TGF-β 1 signaling, promotes islet β cell proliferation in adult mice, supporting the tumor suppressive role of TGF-β/Smad signaling in pNETs [322].…”

“…Nakakura et al, (2005) showed that Ascl1 is upregulated in GI NETs and BON-1 cells. Exogenous overexpression [318,320] or pharmacological activation [223,299,321,322] of Notch1 induces loss of Ascl1, reduction in neuroendocrine markers (synaptophysin and chromogranin), decreased serotonin production by repression of tryptophan hydroxylase (TPH1), and growth inhibition of BON-1 and H727 cells. The HDAC inhibitor, VPA, can also upregulate Notch1 in NET cells through unclear mechanisms [323].…”

“…(iv) TGF-β and SMADs Transforming growth factor-β (TGF-β) superfamily proteins, TGF-β 1 , β 2 , and β 3 , interact with transmembrane receptor serine threonine kinases, TGF-βRI and TGF-βRII, to phosphorylate and activate key downstream transcription factors, SMAD2-4 [321,331]. Target genes of SMADs regulate cell differentiation (including that of the endocrine pancreas) and proliferation [322,331]. Activation of TGF-β signaling can induce or inhibit cell pro-liferation depending on the state of cell differentiation or transformation [331].…”