PREP1 induces EMT by controlling the TGF-?–SMAD3 pathway

Mitochondrion, just like the cellular power plants, generates most of the cell's supply of ATP. Mitophagy is an organelle-speci?c type of autophagy that facilitates the removal of damaged mitochondria through selective targeting of such mitochondria to the autophagic pathway. There are reports that Parkin and PINK1 directly interact, and loss of either Parkin or PINK1 completely abrogates mitophagy. Here, we show that Parkin-dependent mitophagy is antagonized by prosurvival members of the Bcl-2.

Firstly, Parkin becomes localized to depolarized mitochondria in a PINK1-dependent manner and polyubiquitinates multiple mitochondrial outer membrane proteins. Using the CCCP led to rapid translocation of tag-Parkin from the cytosol to mitochondria within several hours of treatment.

As Bcl-2 family proteins regulate mitochondrial outer membrane permeabilization during apoptosis and can also in?uence macroautophagy via interactions with Beclin-1. Bcl-2 proteins suppressed mitophagy through binding to Parkin/PINK1 complexes and inhibiting Parkin translocation to depolarized mitochondria, thereby blocking Parkin-dependent ubiquitination of mitochondrial targets.

To summary, the ability of Bcl-2 proteins to regulate diverse parts of mitochondrial function, including the removal of impaired mitochondria via Parkin/PINK1-dependent mitophagy, as we have shown here, suggests that the Bcl-2 family act as global regulators of mitochondrial network homeostasis.

Epithelial–mesenchymal transition (EMT) is defined as the transformation of polarized epithelial cancer cells into highly motile mesenchymal derivatives responsible for tumor invasion. EMT is controlled by complex networks of transcription factors responsive to paracrine factors such as TGF-?. Prep1 is a tumor suppressor that inhibits neoplastic transformation by competing with myeloid ecotropic integration site 1 for binding to the common heterodimeric partner Pbx1. Here, we report that PREP1 is a novel EMT inducer and prometastatic transcription factor.

Firstly, PREP1 overexpression is sufficient to trigger EMT, whereas PREP1 down-regulation inhibits the induction of EMT in response to TGF-?. TGF-? represents a major tumor suppressor cytokine.

Decreased Prep1 expression results in increased apoptosis in Prep1 embryos and mouse embryonic fibroblasts.

Next, we show that PREP1 induces the nuclear accumulation of SMAD3. Nuclear localization of regulatory SMADs (R-SMADs) requires TGFBR1-mediated C-terminal phosphorylation and formation of heteromeric complexes with SMAD4.

These studies build important prognostic relevance in a cancer in which prognostic markers are badly needed. To summary, the positive staining of PREP1 in brain metastasis derived from several kinds of human cancer suggests that PREP1 might be an EMT inducer in different cellular contexts.

Numerologist Warda is hooked on OG-L002 fishing, collecting. And lastly her encouragement comes from socializing along with her companions.