DAP5 Promotes Cap-Independent Translation of Bcl-2 and CDK1 to Facilitate Cell Survival during Mitosis

Marash, Lea; Liberman, Noa; Henis-Korenblit, Sivan; Sivan, Gilad; Reem, Eran; Elroy‐Stein, Orna; Kimchi, Adi

doi:10.1016/j.molcel.2008.03.018

Cited by 134 publications

(141 citation statements)

References 44 publications

Supporting

Mentioning

135

Contrasting

Order By: Relevance

“…Accordingly, recent reports have shown that p97 stimulates c-myc IRES activity in vitro (Hundsdoerfer et al 2005), enhances capindependent translation of pro-survival factors during mitosis (Marash et al 2008), and modulates alternative translation initiation during endoplasmic reticulum stress (Lewis et al 2008). Thus, p97 and Ct may exert similar effects on cap-independent translation of c-myc or VEGF mRNA in vivo.…”

Section: Discussionmentioning

confidence: 99%

Activation of cap-independent translation by variant eukaryotic initiation factor 4G in vivo

Kaiser¹,

Dobrikova²,

Bradrick³

et al. 2008

RNA

View full text Add to dashboard Cite

Protein synthesis is tightly controlled by assembly of an intricate ribonucleoprotein complex at the m 7 GTP-cap on eukaryotic mRNAs. Ensuing linear scanning of the 59 untranslated region (UTR) is believed to transfer the preinitiation complex to the initiation codon. Eukaryotic mRNAs are characterized by significant 59 UTR heterogeneity, raising the possibility of differential control of translation initiation rate at individual mRNAs. Curiously, many mRNAs with unconventional, highly structured 59 UTRs encode proteins with central biological roles in growth control, metabolism, or stress response. The 59 UTRs of such mRNAs may influence protein synthesis rate in multiple ways, but most significantly they have been implicated in mediating alternative means of translation initiation. Cap-independent initiation bypasses strict control over the formation of initiation intermediates at the m 7 GTP cap. However, the molecular mechanisms that favor alternative means of ribosome recruitment are not understood. Here we provide evidence that eukaryotic initiation factor (eIF) 4G controls cap-independent translation initiation at the c-myc and vascular endothelial growth factor (VEGF) 59 UTRs in vivo. Cap-independent translation was investigated in tetracycline-inducible cell lines expressing either full-length eIF4G or a C-terminal fragment (Ct) lacking interaction with eIF4E and poly(A) binding protein. Expression of Ct, but not intact eIF4G, potently stimulated cap-independent initiation at the c-myc/VEGF 59 UTRs. In vitro RNA-binding assays suggest that stimulation of cap-independent translation initiation by Ct is due to direct association with the c-myc/VEGF 59 UTR, enabling 43S preinitiation complex recruitment. Our work demonstrates that variant translation initiation factors enable unconventional translation initiation at mRNA subsets with distinct structural features.

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of cap-independent translation by variant eukaryotic initiation factor 4G in vivo

Kaiser¹,

Dobrikova²,

Bradrick³

et al. 2008

RNA

View full text Add to dashboard Cite

show abstract

“…Previous reports established the neuroprotective effect of Bcl-2 in neurons. [61][62][63] HuR has also been linked to the activation of prosurvival Bcl-2 family members 56,64,65 through the regulation of their turnover and translation, 56,[66][67][68] In HT-22 cells, HuR maintains Bcl2 mRNA stability and translation at a constant rate to buffer its requirement during assault and preserve mitochondrial homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection requires the functions of the RNA-binding protein HuR

et al. 2014

View full text Add to dashboard Cite

Alterations in the functions of neuronal RNA-binding proteins (RBPs) can contribute to neurodegenerative diseases. However, neurons also express a set of widely distributed RBPs that may have developed specialized functions. Here, we show that the ubiquitous member of the otherwise neuronal Elavl/Hu family of RNA-binding proteins, Elavl1/HuR, has a neuroprotective role. Mice engineered to lack exclusively HuR in the hippocampal neurons of the central nervous system (CNS), maintain physiologic levels of neuronal Elavls and develop a partially diminished seizure response following strong glutamatergic excitation; however, they display an exacerbated neurodegenerative response subsequent to the initial excitotoxic event. This response was phenocopied in hippocampal cells devoid of ionotropic glutamate receptors in which the loss of HuR results in enhanced mitochondrial dysfunction, oxidative damage and programmed necrosis solely after glutamate challenge. The molecular dissection of HuR and nElavl mRNA targets revealed the existence of a HuR-restricted posttranscriptional regulon that failed in HuR-deficient neurons and is involved in cellular energetics and oxidation defense. Thus, HuR acts as a specialized controller of oxidative metabolism in neurons to confer protection from neurodegeneration.

show abstract

“…cDNA was measured by q-RT-PCR using the QuantiTect SYBR Green PCR Kit (Qiagen). Primers were designed from previous publications; for p53, 18 Bcl-2 17 and DAP5, 17 glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA levels served as an endogenous control. All real-time q-RT-PCR experiments were performed in triplicate with no-template as a negative control.…”

Section: Methodsmentioning

confidence: 99%

“…15,16 It has been reported that DAP5 regulates IRES-driven translation of Bcl-2 (B-cell lymphoma 2), p53, XIAP (X-linked inhibitor of apoptosis protein), CDK1 (cyclin-dependent kinase 1), c-Myc and other IRES-containing genes under conditions of stress, growth and apoptosis. [17][18][19] DAP5 mRNA also contains an IRES in its 5′-UTR, and is proficient in promoting its own translation, generating a positive feedback loop for its expression. 14,15 Additionally, DAP5 may undergo post-translational modifications, such as cleavage by caspases during apoptosis, generating a truncated, yet functional 86-kDa form of DAP5 that is more potent and efficient at translation initiation.…”

mentioning

confidence: 99%

Cleavage of DAP5 by coxsackievirus B3 2A protease facilitates viral replication and enhances apoptosis by altering translation of IRES-containing genes

Hanson

Qiu

et al. 2015

Cell Death Differ

View full text Add to dashboard Cite

Cleavage of eukaryotic translation initiation factor 4G (eIF4G) by enterovirus proteases during infection leads to the shutoff of cellular cap-dependent translation, but does not affect the initiation of cap-independent translation of mRNAs containing an internal ribosome entry site (IRES). Death-associated protein 5 (DAP5), a structural homolog of eIF4G, is a translation initiation factor specific for IRES-containing mRNAs. Coxsackievirus B3 (CVB3) is a positive single-stranded RNA virus and a primary causal agent of human myocarditis. Its RNA genome harbors an IRES within the 5′-untranslated region and is translated by a cap-independent, IRES-driven mechanism. Previously, we have shown that DAP5 is cleaved during CVB3 infection. However, the protease responsible for cleavage, cleavage site and effects on the translation of target genes during CVB3 infection have not been investigated. In the present study, we demonstrated that viral protease 2A but not 3C is responsible for DAP5 cleavage, generating 45-and 52-kDa N-(DAP5-N) and C-terminal (DAP5-C) fragments, respectively. By site-directed mutagenesis, we found that DAP5 is cleaved at amino acid G434. Upon cleavage, DAP5-N largely translocated to the nucleus at the later time points of infection, whereas the DAP5-C largely remained in the cytoplasm. Overexpression of these DAP5 truncates demonstrated that DAP5-N retained the capability of initiating IRES-driven translation of apoptosis-associated p53, but not the prosurvival Bcl-2 (B-cell lymphoma 2) when compared with the full-length DAP5. Similarly, DAP5-N expression promoted CVB3 replication and progeny release; on the other hand, DAP5-C exerted a dominant-negative effect on cap-dependent translation. Taken together, viral protease 2A-mediated cleavage of DAP5 results in the production of two truncates that exert differential effects on protein translation of the IRES-containing genes, leading to enhanced host cell death. Coxsackievirus B3 (CVB3), a primary cause of viral myocarditis, is associated with sudden, unexpected death, 1 dilated cardiomyopathy and heart failure. 2 The CVB3 genome consists of a single open reading frame, which is translated to a polyprotein, and subsequently processed by viral proteases 2A and 3C. Similar to other picornaviruses, the CVB3 genome is linked to a small viral peptide, Vpg, rather than a 7-methyl guanosine cap structure at its 5′ terminus. Thus, CVB3 RNA is translated by a cap-independent mechanism and is driven by an internal ribosome entry site (IRES) harbored in the 5′ untranslated region (5′-UTR). 3,4 Viral proteases actively suppress multiple host cell activities that help the virus evade host defense mechanisms, promote viral replication and promote host cell apoptosis. For example, enterovirus proteases can cleave eukaryotic translation initiation factors 4GI (eIF4GI) 5-7 and eIF4GII. 8,9 Picornavirus proteases have also been reported to cleave other canonical translation initiation factors in the cap-dependent translation initiation complex, such as eIF5B 10 and ...

show abstract

DAP5 Promotes Cap-Independent Translation of Bcl-2 and CDK1 to Facilitate Cell Survival during Mitosis

Cited by 134 publications

References 44 publications

Activation of cap-independent translation by variant eukaryotic initiation factor 4G in vivo

Activation of cap-independent translation by variant eukaryotic initiation factor 4G in vivo

Neuroprotection requires the functions of the RNA-binding protein HuR

Cleavage of DAP5 by coxsackievirus B3 2A protease facilitates viral replication and enhances apoptosis by altering translation of IRES-containing genes

Contact Info

Product

Resources

About