MADD Is a Downstream Target of PTEN in Triggering Apoptosis

Abstract

Mitogen-activated kinase activating death domain containing protein (MADD) is abundantly expressed in cancer cells and necessary for maintaining cancer cell survival. However, this survival function of MADD is dependent upon its phosphorylation by protein kinase B (Akt). The tumour suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a lipid phosphatase that negatively regulates the phosphatidylinositol 3-kinase (PI3K)-Akt signalling pathway. The downstream targets of PTEN in triggering apoptosis have not yet been completely identified. Here, we report that MADD can act as a pro-apoptotic factor to initiate apoptosis when its phosphorylation is attenuated by PTEN. Our data show that tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) induced a reduction in MADD phosphorylation with a concomitant up-regulation of PTEN. Knock down of PTEN using a specific siRNA prevented TRAIL-induced reduction in pMADD levels. Surprisingly, Akt non-phopshorylated MADD translocated from the plasma membrane to cytoplasm where it bound to 14-3-3 and displaced 14-3-3 associated Bax, which translocated to mitochondria resulting in cytochrome-C release. Taken together, our data reveal that PTEN can convey the death signal by preventing MADD phosphorylation by Akt.

Transient stabilization, rather than inhibition, of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma

“…While Thr366 phosphorylation is thought to lead to PTEN destabilization [35], the contribution of Ser-362 phosphorylation to PTEN function is not known. Given that this tumor suppressor is known to contribute to both intrinsic survival pathways [36] and the extrinsic cell death pathways [37,38], the overall effect of GSK-3βi on therapeutic apoptosis in B-lymphoid malignancies would have been difficult to predict with certainty. The fact that one of its key targets Myc has manifold effects on tumor cell survival only adds to the complexity of this system.…”

CircRNA_0000429 Regulates Development of NSCLC by Acting as a Sponge of miR-1197 to Control MADD

“… 24 Meanwhile, MADD is a downstream target of PTEN in triggering apoptosis. 25 Further investigations revealed that miR-1197 overexpression-caused decreases in cell proliferation, migration and invasion were significantly prevented by overexpression of MADD. The results indicated that miR-1197 exerted its tumor suppresser effects by targeting MADD in NSCLC.…”

Maternal high-fat diet induces hyperproliferation and alters Pten/Akt signaling in prostates of offspring

“…This would be most prevalent in older subjects, which had highly elevated hyperplasia rates. Second, given that Pten regulates apoptosis 37 , HFD could concurrently deregulate hyperplasia and apoptosis by deregulating Pten activity. Finally, gestational diet could deregulate both Pten/Akt-driven proliferation and another independent pathway, leading to an upshift in apoptosis.…”