STAT3 and MCL-1 associate to cause a mesenchymal epithelial transition

Abstract

Embryo implantation is effected by a myriad of signaling cascades acting on the embryo-endometrium axis. Here we show, by using MALDI TOF analysis, far-western analysis and colocalization and co-transfection studies, that STAT3 and MCL-1 are interacting partners during embryo implantation. We show in vitro that the interaction between the two endogenous proteins is strongly regulated by estrogen and progesterone. Implantation, pregnancy and embryogenesis are distinct from any other process in the body, with extensive, but controlled, proliferation, cell migration, apoptosis, cell invasion and differentiation. Cellular plasticity is vital during the early stages of development for morphogenesis and organ homeostasis, effecting the epithelial to mesenchymal transition (EMT) and, the reverse process, mesenchymal to epithelial transition (MET). STAT3 functionally associates with MCL-1 in the mammalian breast cancer cell line MCF7 that overexpresses STAT3 and MCL-1, which leads to an increased rate of apoptosis and decreased cellular invasion, disrupting the EMT. Association of MCL-1 with STAT3 modulates the normal, antiapoptotic, activity of MCL-1, resulting in pro-apoptotic effects. Studying the impact of the association of STAT3 with MCL-1 on MET could lead to an enhanced understanding of pregnancy and infertility, and also metastatic tumors.

miR-339-3p Is a Tumor Suppressor in Melanoma

“…Moreover, MCL1 is functionally involved in melanoma cell survival, cell death induction, proliferation, and EMT (31,47) and was described to interfere with anoikis induction, resulting in enhanced cancer cell dissemination (48,49). Anoikis, a cell death program activated upon cell-cell or cell-extracellular matrix contact loss, represents one hallmark of cancer, promoting tumor cell migration and invasion (6,50).…”

“…28,29). This oncogene has been widely investigated with special focus on its functional role in apoptosis, cell survival, and epithelial mesenchymal transformation in various malignancies (30,31). However, nothing has been published on the function of MCL1 in melanoma cell invasion, so far.…”

Epithelial-to-Mesenchymal Transition in the Female Reproductive Tract: From Normal Functioning to Disease Pathology

“…A direct interaction between the transcription factor, STAT3 and MCL-1, a gene discovered to be expressed in cells committed to differentiation, has been proposed to be responsible. This is due to the fact that in the presence of the steroid hormones, estrogen and progesterone, MCL-1 and STAT3 can co-localize to the nucleus and modulate the promoter activity of STAT3 (83). Overexpression of the two proteins prevents EMT and leads to an increase in epithelial markers along with a concurrent downregulation of mesenchymal markers (83).…”

“…This is due to the fact that in the presence of the steroid hormones, estrogen and progesterone, MCL-1 and STAT3 can co-localize to the nucleus and modulate the promoter activity of STAT3 (83). Overexpression of the two proteins prevents EMT and leads to an increase in epithelial markers along with a concurrent downregulation of mesenchymal markers (83). As co-localization of MCL-1 and STAT3 is most evident in stromal cells post-implantation, during decidualization, these two factors have been implicated in the EMT to MET shift necessary for successful embryo implantation (83).…”

Myeloid cell leukemia 1 (MCL-1), an unexpected modulator of protein kinase signaling during invasion

“…45 Additionally, MCL-1 and STAT3 have been shown to interact during embryonic implantation, which resulted in the expression of epithelial to mesenchymal markers, increased apoptosis and decreased invasion. 46 MCL-1 is highly expressed in both human and mouse embryonic stem cells (ESCs), with the loss of MCL-1 through siRNA or up-regulation of NOXA by CDK1 inhibitor treatment leading to significant induction of cell death, pointing to MCL-1 playing an active role in ESC homeostasis. 47 The divergent roles of MCL-1 are dependent on its post-translational modification and protein-protein interactions.…”