Accumulation of Sequence-specific RNA-binding Proteins in the Cytosol of Activated T Cells Undergoing RNA Degradation and Apoptosis

Mondino, Anna; Jenkins, Marc K.

doi:10.1074/jbc.270.44.26593

Cited by 27 publications

(21 citation statements)

References 51 publications

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“…6 and data not shown) (19), and it may induce apoptosis by regulating or interfering with the translation and/or mRNA stability of apoptotic or survival proteins. There is a precedent for these mechanisms, since an increase in RNA degradation before the onset of apoptosis has been observed in T cells (28,37) and hnRNP K has been shown to regulate translation (30).…”

Section: Discussionmentioning

confidence: 99%

Structure-Function Analysis of Qk1: a Lethal Point Mutation in Mouse quaking Prevents Homodimerization

Chen

Richard

1998

Molecular and Cellular Biology

112

131

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Qk1 is a member of the KH domain family of proteins that includes Sam68, GRP33, GLD-1, SF1, and Who/How. These family members are RNA binding proteins that contain an extended KH domain embedded in a larger domain called the GSG (for GRP33-Sam68-GLD-1) domain. An ethylnitrosourea-induced point mutation in the Qk1 GSG domain alters glutamic acid 48 to a glycine and is known to be embryonically lethal in mice. The function of Qk1 and the GSG domain as well as the reason for the lethality are unknown. Here we demonstrate that the Qk1 GSG domain mediates RNA binding and Qk1 self-association. By using in situ chemical cross-linking studies, we showed that the Qk1 proteins exist as homodimers in vivo. The Qk1 self-association region was mapped to amino acids 18 to 57, a region predicted to form coiled coils. Alteration of glutamic acid 48 to glycine (E¦G) in the Qk1 GSG domain (producing protein Qk1:E¦G) abolishes self-association but has no effect on the RNA binding activity. The expression of Qk1 or Qk1:E¦G in NIH 3T3 cells induces cell death by apoptosis. Approximately 90% of the remaining transfected cells are apoptotic 48 h after transfection. Qk1:E¦G was consistently more potent at inducing apoptosis than was wild-type Qk1. These results suggest that the mouse quaking lethality (E¦G) occurs due to the absence of Qk1 self-association mediated by the GSG domain.

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Section: Discussionmentioning

confidence: 99%

Structure-Function Analysis of Qk1: a Lethal Point Mutation in Mouse quaking Prevents Homodimerization

Chen

Richard

1998

Molecular and Cellular Biology

112

131

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“…11 Third, RNA turnover may have the general role of breaking down cellular components to facilitate recycling after apoptotic cells are phagocytosed. 31 Additionally the studies by Mondino and Jenkins 31 have shown that there is an accumulation of cytosolic RNAbinding proteins in apoptotic cells. Several of these binding proteins recognize AU-rich sequences known to influence RNA stability.…”

Section: Discussionmentioning

confidence: 99%

28S ribosome degradation in lymphoid cell apoptosis: evidence for caspase and Bcl-2-dependent and -independent pathways

et al. 2000

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Apoptosis, a physiological form of cell death, is characterized by the activation of a program that kills cells and recycles their constituents. We have used thymoma cell lines to examine the role of Bcl-2 and caspases in ribosomal destruction during apoptosis. Glucocorticoid-and calcium ionophore (A23187)-induced apoptosis of S49 Neo cells resulted in both 28S rRNA and DNA degradation. Interestingly, anisomycin, a potent protein synthesis inhibitor, also induced 28S rRNA and DNA fragmentation suggesting that the responsible nucleases are present in the viable cells and become activated during apoptosis. The anti-apoptotic protein, Bcl-2, inhibited both glucocorticoid-and anisomycin-induced DNA and 28S rRNA degradation but could not protect against A23187-induced nucleic acid degradation. We next examined the role of caspase activation in the generation of 28S rRNA degradation through the use of ZVAD, a general caspase inhibitor. Under conditions where ZVAD substantially decreased 28S rRNA degradation induced by glucocorticoid or anisomycin, no decrease was observed when A23187 was used to induce apoptosis. Surprisingly, RNA degradation, like DNA degradation, occurs exclusively in shrunken lymphocytes but not those with normal cell volume despite equivalent exposure of the cells to the apoptotic signals. Together, these findings indicate the ribosome is a specific target for death effectors during apoptosis and that a caspase/Bcl-2-independent pathway exists to activate its destruction. Cell Death and Differentiation (2000) 7, 994 ± 1001.

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“…27,29 Finally, massive degradation of cellular mRNAs and 28S rRNA take place and further contribute to the translational block under the cell death circumstances. [57][58][59] All these scenarios are described in detail in other chapters of this issue of CDD.…”

Section: Switching the Initiation Of Protein Synthesis From Cap-depenmentioning

confidence: 99%

“…It turned out that this cDNA fragment codes for a fragment of the protein, that is, a miniprotein encompassing amino acids 522-776 from the C-terminal region of the full-length protein ( Figure 1). The sequence of the full-length protein shared strong homology to eIF4G (58) and placed this novel gene within this family of scaffold proteins, which has since expanded to also include the PAIPs. 65,66 In addition, detailed sequence alignments showed that the region corresponding to the rescued miniprotein was less conserved within the family members ( Figure 1).…”

Section: Dap5/p97/nat1 -The Discovery Of the Gene And Initial Structumentioning

confidence: 99%

DAP5 and IRES-mediated translation during programmed cell death

Marash

Kimchi

2005

Cell Death Differ

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DAP5 (Death Associated Protein 5), also named p97 and NAT1, is a member of the eIF4G family that lacks the eIF4E binding site. Its function was linked to programmed cell death (PCD) based on the seminal finding that a fragment of DAP5/ p97 protein, which acted in a dominant-negative manner, protected against IFN-gamma (IFN-g)-induced cell death. Subsequently, it was found that DAP5 protein is activated during cell death by caspase cleavage, yielding a C-terminaltruncated protein of 86 kDa. The p86 form promotes internal ribosome entry site (IRES)-dependent translation of several mRNAs including Apaf-1, c-myc, XIAP, HIAP2 and DAP5 itself, which carries an IRES element in its 5 0 UTR. The activation of DAP5 IRES creates a positive feedback loop, which results in sustained translation of DAP5 protein during PCD under conditions of reduced cap-dependent translation. DAP5 deficiency prevents embryonic stem (ES) cell differentiation, suggesting a wider range of DAP5 mRNA targets and additional mechanisms that might activate the protein.

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Accumulation of Sequence-specific RNA-binding Proteins in the Cytosol of Activated T Cells Undergoing RNA Degradation and Apoptosis

Cited by 27 publications

References 51 publications

Structure-Function Analysis of Qk1: a Lethal Point Mutation in Mouse quaking Prevents Homodimerization

Structure-Function Analysis of Qk1: a Lethal Point Mutation in Mouse quaking Prevents Homodimerization

28S ribosome degradation in lymphoid cell apoptosis: evidence for caspase and Bcl-2-dependent and -independent pathways

DAP5 and IRES-mediated translation during programmed cell death

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