DAPk1 inhibits NF-κB activation through TNF-α and INF-γ-induced apoptosis

Yoo, Heon Jong; Byun, Hyun Jung; Kim, Boh Ram; Lee, Ki Hwan; Park, Soo‐Jin; Rho, Seung Bae

doi:10.1016/j.cellsig.2012.03.010

Cited by 64 publications

(53 citation statements)

References 51 publications

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“…We tested the expression of apoptosis-regulating genes Traf2, Traf6, Parp1, Atf6, Ask1, Ask2, Dapk1, and Apaf1 in siBrg1 NCCs (21)(22)(23)(24)(25)(26)(27)(28). Of these genes, only Ask1 (apoptosis signal-regulating kinase 1) exhibited increased expression (a 1.65-fold increase; P < 0.03) in siBrg1NCCs; the other genes showed no significant changes (Fig.…”

Section: Resultsmentioning

confidence: 99%

Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development

Xiong²,

Shang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Development of the cerebral vessels, pharyngeal arch arteries (PAAs). and cardiac outflow tract (OFT) requires multipotent neural crest cells (NCCs) that migrate from the neural tube to target tissue destinations. Little is known about how mammalian NCC development is orchestrated by gene programming at the chromatin level, however. Here we show that Brahma-related gene 1 (Brg1), an ATPase subunit of the Brg1/Brahma-associated factor (BAF) chromatin-remodeling complex, is required in NCCs to direct cardiovascular development. Mouse embryos lacking Brg1 in NCCs display immature cerebral vessels, aberrant PAA patterning, and shortened OFT. Brg1 suppresses an apoptosis factor, Apoptosis signal-regulating kinase 1 (Ask1), and a cell cycle inhibitor, p21 cip1 , to inhibit apoptosis and promote proliferation of NCCs, thereby maintaining a multipotent cell reservoir at the neural crest. Brg1 also supports Myosin heavy chain 11 (Myh11) expression to allow NCCs to develop into mature vascular smooth muscle cells of cerebral vessels. Within NCCs, Brg1 partners with chromatin remodeler Chromodomain-helicase-DNAbinding protein 7 (Chd7) on the PlexinA2 promoter to activate PlexinA2, which encodes a receptor for semaphorin to guide NCCs into the OFT. Our findings reveal an important role for Brg1 and its downstream pathways in the survival, differentiation, and migration of the multipotent NCCs critical for mammalian cardiovascular development.N eural crest cells (NCCs) originate from the neural crest of the dorsal neural tube and migrate to many regions of the embryo, where they differentiate into a variety of local cells, including cardiovascular tissues (1). NCCs that emigrate from the neural crest of rhombomere 6-8 to pharyngeal arches and the heart are essential for the patterning of pharyngeal arch arteries (PAAs) and the cardiac outflow tract (OFT) (2, 3). These NCCs also differentiate into vascular smooth muscle cells (SMCs) of PAAs and the muscular septum of the aorta and pulmonary trunk (4, 5). In contrast, NCCs from the cephalic neural tube migrate to the face and forebrain to form craniofacial bones, as well as SMCs of facial and forebrain vessels (6). Thus, NCCs are critical for the formation of cardiac OFT and vascular supplies of large areas of the body.Disruption of NCC development, either directly or indirectly, results in many forms of human birth defects with cardiovascular malformations, including Alagille, Carpenter, Ivemark, Leopard, Williams, DiGeorge, and CHARGE syndromes (7). These syndromes involve defects in PAAs or cardiac OFT, such as coarctation of the aorta, interrupted aortic arch, pulmonary artery stenosis, double-outlet right ventricle, tetralogy of Fallot, or persistent truncus arteriosus. During PAA and OFT development, NCCs are regulated by numerous transcription factors, including Pax3, Pbx1/2/3, Tbx1/2/3/20, Msx1/2, Hand2, AP2a, Cited2, Pitx2, Sox4, Foxc1/c2/d3/h1, Fog2, Gata3/4/6, and Notch/NICD (8). Such extensive involvement of transcription factors indicates the importance of gene pr...

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Section: Resultsmentioning

confidence: 99%

Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development

Xiong²,

Shang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Using DR5 promoter luciferase constructs with either wild-type (wt) or NF-kB-mt consensus sites, we established the necessity of NF-kB as a transcription factor required for the induction of DR5 in response to DAPK2 depletion. Recently, Yoo et al 29 suggested that DAPK1 could function as a repressor for NF-kB activation. 29 Additionally, NF-kB activation downstream of T-cell receptor signalling is increased in DAPK1-knockout cells.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Yoo et al 29 suggested that DAPK1 could function as a repressor for NF-kB activation. 29 Additionally, NF-kB activation downstream of T-cell receptor signalling is increased in DAPK1-knockout cells. 30 As all DAPKs are thought to form multiprotein complexes, 31 the activation of NF-kB proteins upon DAPK2 knockdown is likely to be caused by at least some of the same molecular events described for DAPK1.…”

Section: Discussionmentioning

confidence: 99%

DAPK2 is a novel modulator of TRAIL-induced apoptosis

Stöcker

et al. 2014

Cell Death Differ

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Targeting molecules involved in TRAIL-mediated signalling has been hailed by many as a potential magic bullet to kill cancer cells efficiently, with little side effects on normal cells. Indeed, initial clinical trials showed that antibodies against TRAIL receptors, death receptor (DR)4 and DR5, are well tolerated by cancer patients. Despite efficacy issues in the clinical setting, novel approaches to trigger TRAIL-mediated apoptosis are being developed and its clinical potential is being reappraised. Unfortunately, as observed with other cancer therapies, many patients develop resistance to TRAIL-induced apoptosis and there is thus impetuous for identifying additional resistance mechanisms that may be targetable and usable in combination therapies. Here, we show that the death-associated protein kinase 2 (DAPK2) is a modulator of TRAIL signalling. Genetic ablation of DAPK2 using RNA interference causes phosphorylation of NF-jB and its transcriptional activity in several cancer cell lines. This then leads to the induction of a variety of NF-jB target genes, which include proapoptotic DR4 and DR5. DR4 and DR5 protein expression is correspondingly increased on the cell surface and this leads to the sensitisation of resistant cells to TRAILinduced killing, in a p53-independent manner. As DAPK2 is a kinase, it is imminently druggable, and our data thus offer a novel avenue to overcome TRAIL resistance in the clinic. Despite the effort and resources invested in cancer research, cancer remains a serious public health problem. Most patients are treated surgically, with chemotherapeutic drugs and/or antibodies and small molecule inhibitors. Patients generally respond well to the initial therapy but frequently develop resistance to it. This poses a challenge to their treatment and calls for alternative approaches to be developed. Indeed, much excitement was generated in the mid-1990s when tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was identified. [1][2][3][4] TRAIL is a death receptor (DR) ligand that signals through DR4 and DR5, two members of the TNF receptor family. 5-7 DR5 has two isoforms that differ by 29 amino acids and which are functionally indistinguishable. 5,8 TRAIL ligation activates primarily the extrinsic apoptotic pathway. The formation of ligand/receptor complexes leads to the assembly of a multiprotein death-inducing signalling complex (DISC), which in the case of TRAIL is typically composed of the adaptor Fasassociated death domain, caspase-8, caspase-10 and/or c-FLIP. These initiator caspases proteolytically cleave effector caspases such as caspase-3, caspase-6 and/or caspase-7 thereby activating them. This leads to the destruction of key cellular components and the appearance of typical features of apoptosis. TRAIL can also activate intrinsic apoptotic pathways via BID and thus involve mitochondria. By virtue of preferentially killing tumour cells, TRAIL is seen by many as a 'magic bullet' against cancer cells. Some cancer cells, however, are resistant, or develop resistanc...

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“…Indeed, DAPK1 expression is downregulated in multiple cancer types (24,25), and it is known to be an important mediator of death-inducing signals (8,(26)(27)(28). In particular, TNF-α and IFN-γ activate DAPK1-mediated cell death, possibly through inhibition of NF-κB (29). DAPK1 is reported to both directly transactivate p53 (30) and to be a transcriptional target of p53 (31).…”

Section: Inhibition Of Dapk1 Suppresses P53-mutant But Not P53-wt Brementioning

confidence: 99%