Three-amino-acid-loop-extension homeodomain factor Meis3 regulates cell survival via PDK1

Abstract

Three-amino-acid-loop-extension (TALE) homeodomain proteins including Meis and Pbx families are generally recognized for their roles in growth and differentiation during vertebrate embryogenesis and tumorigenesis. Whereas genetic studies indicate that Pbx1 regulates the development and function of insulin-producing pancreatic β-cells, the role of Meis family members in β-cells is still unknown. Here we show that Meis3 is abundantly expressed in pancreatic islets and β-cells and that it regulates β-cell survival. We further identify the 3-phosphoinositide-dependent protein kinase 1 (PDK1), a well-known kinase involved in the PI3K-Akt signaling pathway, as a direct Meis3 target, which mediates its role in β-cell survival. This regulatory module appears to function broadly as we also identify Meis3 regulation of cell survival and PDK1 expression in ovarian carcinoma cells, suggesting a unique function for Meis3 beyond the traditional roles for TALE homeodomain factors during embryogenesis.diabetes | transcription | pancreas | apoptosis

The PDK1 master kinase is over-expressed in acute myeloid leukemia and promotes PKC-mediated survival of leukemic blasts

“…In support of this, overexpression of PDK1 has been implicated in the development of prostate and pancreatic cancer in vivo 25,[33][34][35] and has been shown to transform mouse mammary epithelial cells in vitro. 36 The mechanism of overexpression is unclear; it has been reported that Meis3 up-regulated PDK1 transcription; 37 however, in our microarray database of 205 AML patients we found no correlation between Meis3 and PDK1 mRNA expression which also correlated poorly with PDK1 protein levels (data not shown). This observation is in accord with our previous data that suggested that PDK1 overexpression in this context arises from a post-translation mechanism.…”

A Bovine Lymphosarcoma Cell Line Infected with Theileria annulata Exhibits an Irreversible Reconfiguration of Host Cell Gene Expression

“…MEIS3 is up-regulated 65-fold by parasite infection and reversed with BW720c (confirmed by RT-PCR). A known direct target of MEIS3 is the 3-phosphoinositide-dependent protein kinase 1 (PDK1) involved in PI3-K-AKT signalling, engendering an anti-apoptotic role for MEIS3 [51]. Defined HOX targets are functionally wide ranging (reviewed in [52]) and include the CDK inhibitor p21, OPN (osteopontin), and bFGF (basic fibroblast growth factor).…”

MicroRNA-7 Regulates the mTOR Pathway and Proliferation in Adult Pancreatic β-Cells

“…Mouse islets were isolated from 6- to 7-week-old wild-type C57/Bl6 males using collagenase digestion as previously described (32). Isolated islets were trypsinized (0.05% Trypsin) and plated as a monolayer onto poly- l -lysine-coated six-well dishes or four-well chambers, followed by transfection (Lipofectamine 2000) with 40 nmol/L antimiR-7a or control oligonucleotide.…”