Monitoring p53 by MDM2 and MDMX is required for endocrine pancreas development and function in a spatio-temporal manner

Abstract

Although p53 is not essential for normal embryonic development, it plays a pivotal role in many biological and pathological processes, including cell fate determination-dependent and independent events and diseases. The expression and activity of p53 largely depend on its two biological inhibitors, MDM2 and MDMX, which have been shown to form a complex in order to tightly control p53 to an undetectable level during early stages of embryonic development. However, more delicate studies using conditional gene-modification mouse models show that MDM2 and MDMX may function separately or synergistically on p53 regulation during later stages of embryonic development and adulthood in a cell and tissue-specific manner. Here, we report the role of the MDM2/MDMX-p53 pathway in pancreatic islet morphogenesis and functional maintenance, using mouse lines with specific deletion of MDM2 or MDMX in pancreatic endocrine progenitor cells. Interestingly, deletion of MDM2 results in defects of embryonic endocrine pancreas development, followed by neonatal hyperglycemia and lethality, by inducing pancreatic progenitor cell apoptosis and inhibiting cell proliferation. However, unlike MDM2-knockout animals, mice lacking MDMX in endocrine progenitor cells develop normally. But, surprisingly, the survival rate of adult MDMX-knockout mice drastically declines compared to control mice, as blockage of neonatal development of endocrine pancreas by inhibition of cell proliferation and subsequent islet dysfunction and hyperglycemia eventually lead to type 1 diabetes-like disease with advanced diabetic nephropathy. As expected, both MDM2 and MDMX deletion-caused pancreatic defects are completely rescued by loss of p53, verifying the crucial role of the MDM2 and/or MDMX in regulating p53 in a spatio-temporal manner during the development, functional maintenance, and related disease progress of endocrine pancreas. Also, our study suggests a possible mouse model of advanced diabetic nephropathy, which is complementary to other established diabetic models and perhaps useful for the development of anti-diabetes therapies.

p53 induces ARTS to promote mitochondrial apoptosis

“…The primers used for qPCR were 5’-ACCATTGTGGACACACCAGG-3’ and 5’-GAACCTGTGACCACCTGCTA-3’ for human ARTS and 5’-CAGGGCAGGGCTACCACTAG-3’ and 5’-TGATGCAGGGCCTTCATGA-3’ for mouse ARTS. The primers for human and mouse p21 were previously described 30 , 31 .…”

Identification of core genes associated with type 2 diabetes mellitus and gastric cancer by bioinformatics analysis

“…In addition, disruption of p53 function is closely associated with several key BP leading to diabetes, including loss of pancreatic beta cells, interference with glucose homeostasis at the body level, and IR in peripheral tissues. Studies have shown that oxidative stress and elevated levels of free fatty acids lead to activation of p53, which leads to pancreatic beta cell death (20)(21)(22)(23)(24)(25). Meanwhile, p53 can affect peripheral glucose metabolism by directly regulating glucose uptake, glycolysis and gluconeogenesis.…”

RBM10, a New Regulator of p53

“…On the other hand, MDM2 and MDMX can also cooperatively and independently suppress p53 s transcriptional activity by binding to the N-terminal transcriptional domain of p53 via their own N-termini [52]. The mutual dependence of MDM2 and MDMX for their p53-inactivating functions, as well as their essential roles in controlling p53 level and activity in vivo, has been demonstrated in several mouse genetic studies [53][54][55][56][57][58]. Therefore, because both MDM2 and MDMX are p53 responsive transcriptional targets, they play essential roles in controlling p53 level and activity in a negative feedback fashion during embryogenesis and organogenesis.…”