Dataset Information

Smad7 knockdown activates protein kinase RNA-associated eIF2α pathway leading to colon cancer cell death.

ABSTRACT: Upregulation of Smad7, an inhibitor of transforming growth factor-β1 (TGF-β1), occurs in sporadic colorectal cancer (CRC) and knockdown of Smad7 inhibits CRC cell growth, a phenomenon that associates with decreased expression of cell division cycle 25 homolog A and arrest of cells in the S phase of the cell cycle. These findings occur in CRC cells unresponsive to TGF-β1, thus suggesting the existence of a Smad7-mediated TGF-β1-independent mechanism that controls CRC cell behavior. Here we show that Smad7 inhibition with a specific Smad7 antisense oligonucleotide upregulates eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, a transcription factor involved in the regulation of cell cycle arrest and induction of cell death, and induces activating transcription factor 4 (ATF4) and CCAAT/enhancer binding protein homology protein (CHOP), two downstream targets of eIF2α. Among the upstream kinases that control eIF2α phosphorylation, the serine-threonine protein kinase RNA (PKR), but not general control non-derepressible 2 (GCN2) and protein kinase RNA-like endoplasmic reticulum kinase (PERK), is activated by Smad7 knockdown. PKR silencing abolishes Smad7 antisense-induced eIF2α phosphorylation and ATF4/CHOP induction, thereby preventing Smad7 antisense-driven cell death. Smad7 inhibition diminishes interaction of PKR with protein kinase inhibitor p58 (p58^IPK), a cellular inhibitor of PKR, but does not change the expression and/or activity of other factors involved in the control of PKR activation. These findings delineate a novel mechanism by which Smad7 knockdown promotes CRC cell death.

SUBMITTER: De Simone V

PROVIDER: S-EPMC5386514 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Smad7 knockdown activates protein kinase RNA-associated eIF2α pathway leading to colon cancer cell death.

De Simone Veronica V Bevivino Gerolamo G Sedda Silvia S Izzo Roberta R Laudisi Federica F Dinallo Vincenzo V Franzè Eleonora E Colantoni Alfredo A Ortenzi Angela A Salvatori Silvia S Rossi Piero P Sica Giuseppe S GS Fantini Massimo C MC Stolfi Carmine C Monteleone Giovanni G

Cell death & disease 20170316 3

Upregulation of Smad7, an inhibitor of transforming growth factor-β1 (TGF-β1), occurs in sporadic colorectal cancer (CRC) and knockdown of Smad7 inhibits CRC cell growth, a phenomenon that associates with decreased expression of cell division cycle 25 homolog A and arrest of cells in the S phase of the cell cycle. These findings occur in CRC cells unresponsive to TGF-β1, thus suggesting the existence of a Smad7-mediated TGF-β1-independent mechanism that controls CRC cell behavior. Here we show t ...[more]

PMID: 28300830

Similar Datasets

Project description:UnlabelledVirus-induced apoptosis is thought to be the primary mechanism of cell death following reovirus infection. Induction of cell death following reovirus infection is initiated by the incoming viral capsid proteins during cell entry and occurs via NF-κB-dependent activation of classical apoptotic pathways. Prototype reovirus strain T3D displays a higher cell-killing potential than strain T1L. To investigate how signaling pathways initiated by T3D and T1L differ, we methodically analyzed cell death pathways activated by these two viruses in L929 cells. We found that T3D activates NF-κB, initiator caspases, and effector caspases to a significantly greater extent than T1L. Surprisingly, blockade of NF-κB or caspases did not affect T3D-induced cell death. Cell death following T3D infection resulted in a reduction in cellular ATP levels and was sensitive to inhibition of the kinase activity of receptor interacting protein 1 (RIP1). Furthermore, membranes of T3D-infected cells were compromised. Based on the dispensability of caspases, a requirement for RIP1 kinase function, and the physiological status of infected cells, we conclude that reovirus can also induce an alternate, necrotic form of cell death described as necroptosis. We also found that induction of necroptosis requires synthesis of viral RNA or proteins, a step distinct from that necessary for the induction of apoptosis. Thus, our studies reveal that two different events in the reovirus replication cycle can injure host cells by distinct mechanisms.ImportanceVirus-induced cell death is a determinant of pathogenesis. Mammalian reovirus is a versatile experimental model for identifying viral and host intermediaries that contribute to cell death and for examining how these factors influence viral disease. In this study, we identified that in addition to apoptosis, a regulated form of cell death, reovirus is capable of inducing an alternate form of controlled cell death known as necroptosis. Death by this pathway perturbs the integrity of host membranes and likely triggers inflammation. We also found that apoptosis and necroptosis following viral infection are activated by distinct mechanisms. Our results suggest that host cells can detect different stages of viral infection and attempt to limit viral replication through different forms of cellular suicide. While these death responses may aid in curbing viral spread, they can also exacerbate tissue injury and disease following infection.

Dataset Information

Smad7 knockdown activates protein kinase RNA-associated eIF2α pathway leading to colon cancer cell death.

Publications

Smad7 knockdown activates protein kinase RNA-associated eIF2α pathway leading to colon cancer cell death.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets