Cleavage and nuclear translocation of the caspase 3 substrate Rho GDP-dissociation inhibitor, D4-GDI, during apoptosis

Krieser, Ronald J.; Eastman, Alan

doi:10.1038/sj.cdd.4400515

Cited by 66 publications

(48 citation statements)

References 30 publications

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“…However, the function of RhoGDI2 cleavage has only recently been elucidated. Based on the observation that the expression of a non-cleavable RhoGDI2 D19A mutant did not protect CHO cells against apoptosis induction, it was concluded that RhoGDI2 cleavage does not contribute to cell death (22). By contrast, another study suggested that the cleavage of RhoGDI2 by caspase-3 is not a functionally irrelevant effect of caspase activation during apoptosis but rather expedites the progression of the apoptotic process (23).…”

Section: Discussionmentioning

confidence: 99%

RhoGDI2 confers resistance to 5-fluorouracil in human gastric cancer cells

Zheng

et al. 2012

Oncology Letters

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Abstract. Resistance to 5-fluorouracil (5-FU) in patients with gastric cancer is a serious therapeutic problem and major efforts are underway to understand the underlying mechanisms. We have previously identified RhoGDI2 as a contributor to 5-FU resistance in colon cancer cells using 2D electrophoresis and mass spectrometry and the current study aimed to further investigate this role. The expression of RhoGDI2 in seven gastric cancer cell lines was positively correlated with resistance to 5-FU. Lower 5-FU sensitivity of isolated tumor cells from patients with gastric cancer was also associated with higher RhoGDI2 expression. Ectopic expression of RhoGDI2 in gastric cancer cells increased the resistance to 5-FU and reverted low dose 5-FU-induced G2/M phase arrest without affecting the population of sub-G1 cells. Overall, these findings suggest that RhoGDI2 is associated with 5-FU resistance and is a potential therapeutic target for enhancing chemotherapy efficacy in gastric cancer.

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Section: Discussionmentioning

confidence: 99%

RhoGDI2 confers resistance to 5-fluorouracil in human gastric cancer cells

Zheng

et al. 2012

Oncology Letters

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“…Such a localization of caspase-cleaved protein fragments to the nucleus is not uncommon, as we reported recently that the caspase-cleaved form of the Lyn tyrosine kinase is delocalized into the nucleus of cells undergoing apoptosis. 25 Moreover, several other caspase-derived fragments of substrates including FAK, 26 FHOD1, 27 Rho-GDI2, 28 YY1, 29 D4GDJ, 30 Huntingtin 31 and Beclin 1 32 are also targeted into the nucleus in identical circumstances. Of note in the present study, we clearly demonstrated that nuclear localization of DJ-1 Nt is essential for its pro-apoptotic function.…”

Section: Discussionmentioning

confidence: 99%

The caspase 6 derived N-terminal fragment of DJ-1 promotes apoptosis via increased ROS production

et al. 2012

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In pathological conditions, the amount of DJ-1 determines whether a cell can survive or engage a cell death program. This is exemplified in epithelial cancers, in which DJ-1 expression is increased, while autosomal recessive early onset Parkinson's disease mutations of DJ-1 generally lead to decreased stability and expression of the protein. We have shown previously that DJ-1 is cleaved by caspase-6 during induction of apoptosis. We demonstrate here that the N-terminal cleaved fragment of DJ-1 (DJ-1 Nt) is specifically expressed in the nucleus and promotes apoptosis in SH-SY5Y neuroblastoma cell lines. In addition, overexpression of DJ-1 Nt in different cell lines leads to a loss of clonogenic potential and sensitizes to staurosporin and 1-methyl-4-phenylpyridinium (MPP þ )-mediated caspase activation and apoptosis. Importantly, inhibition of endogenous DJ-1 expression with sh-RNA or DJ-1 deficiency mimics the effect of DJ-1 Nt on cell growth and apoptosis. Moreover, overexpression of DJ-1 Nt increases reactive oxygen species (ROS) production, and sensitizes to MPP þ -mediated apoptosis and DJ-1 oxidation. Finally, specific exclusion of DJ-1 Nt from the nucleus abrogates its pro-apoptotic effect. Taken together, our findings identify an original pathway by which generation of a nuclear fragment of DJ-1 through caspase 6-mediated cleavage induces ROS-dependent amplification of apoptosis.

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“…RelA (SC-109), Santa Cruz Biotechnology (Santa Cruz, CA); cytochrome c (clone 7H8.2C12) monoclonal, BD PharMingen (San Diego, CA); Bax (clone 2D2) monoclonal, Zymed Laboratories Inc. (San Francisco, CA); caspase-8 (AAP-118) polyclonal, StressGen Biotechnologies Corporation (Victoria, BC, Canada); p21 WAF1 (clone EA10) monoclonal, Oncogene Research Products (Boston, MA); the D4-GDI polyclonal antibody was developed in this laboratory (19); the Mcl-1 monoclonal antibody and the Bid monoclonal antibody were generously provided by Dr. R. Craig (Dartmouth Medical School, Hanover, NH) and Dr. X. Wang (HHMI, Dallas, TX), respectively. Unless otherwise specified, all other reagents were purchased from Sigma.…”

Section: Methodsmentioning

confidence: 99%

“…Inhibitors-To assess the capacity of ML-1 cells to undergo apoptosis in response to TNF, cells were exposed to TNF in combination with either CHX or act D for 3 h. As an index of apoptotic activity, lysates were immunoblotted for D4-GDI cleavage, a marker of caspase-3 activation (19). A 3-h treatment with either TNF, CHX, or act D alone exhibited no evidence of apoptosis as measured by D4-GDI cleavage (Fig.…”

Section: Tnf Induces Apoptosis In the Presence Of Protein Or Rna Syntmentioning

confidence: 99%

The Novel Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) Potently Enhances Apoptosis Induced by Tumor Necrosis Factor in Human Leukemia Cells

Stadheim¹,

Suh

Ganju

et al. 2002

Journal of Biological Chemistry

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Tumor necrosis factor (TNF) is a potent activator of the nuclear factor-B (NF-B) pathway that leads to upregulation of anti-apoptotic proteins. Hence, TNF induces apoptosis in the presence of inhibitors of protein or RNA synthesis. We report that a novel triterpenoid, 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid (CDDO) inhibits NF-B-mediated gene expression at a step after translocation of activated NF-B to the nucleus. This effect appears specific for the NF-B pathway as CDDO does not inhibit gene expression induced by the phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA). CDDO in combination with TNF caused a dramatic increase in apoptosis in ML-1 leukemia cells that was associated with activation of caspase-8, cleavage of Bid, translocation of Bax, cytochrome c release, and caspase-3 activation. Experiments with caspase inhibitors demonstrated that caspase-8 was an initiator of this pathway. TNF also induced a transient activation of c-Jun N-terminal kinase (JNK), which upon addition of CDDO was converted to a sustained activation. The activation of JNK was also dependent on caspase-8. Sustained activation of JNK is frequently pro-apoptotic, yet inhibition of JNK did not prevent Bax translocation or cytochrome c release, demonstrating its lack of involvement in CDDO/TNF-induced apoptosis. Apoptosis was acutely induced by CDDO/TNF in every leukemia cell line tested including those that overexpress Bcl-x L , suggesting that the mitochondrial pathway is not required for apoptosis by this combination. These results suggest that the apoptotic potency of the CDDO/TNF combination occurs through selective inhibition of NF-B-dependent anti-apoptotic proteins, bypassing potential mitochondrial resistance mechanisms, and thus may provide a basis for the development of novel approaches to the treatment of leukemia. Tumor necrosis factor (TNF)1 induces a broad range of cellular effects including inflammatory responses, NF-B activation, and apoptosis (for review, see Ref. 1). In many systems, the apoptotic potential of TNF is only realized when cells are co-treated with the protein synthesis inhibitor cycloheximide (CHX). This effect of CHX may be caused by inhibition of the translation of NF-B-dependent anti-apoptotic proteins such as TRAF1/2 and c-IAP1/2 (2). Apoptosis induced by TNF is initiated at the membrane where engagement of the tumor necrosis factor receptor results in the recruitment of TRADD and then FADD. A conserved sequence in FADD called the death effector domain serves as a docking site for procaspase-8, which upon activation initiates apoptosis by either of two distinct routes. The first pathway involves caspase-8-directed cleavage of Bid to its active form, tBid, resulting in translocation to the mitochondria and release of cytochrome c into the cytoplasm (3, 4). The released cytoplasmic cytochrome c interacts with caspase-9 and Apaf-1 in the presence of dATP to create the "apoptosome" that serves to cleave and activate caspase-9 (5). Caspase-9 then activates caspase-3, which carries out the exe...

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Cleavage and nuclear translocation of the caspase 3 substrate Rho GDP-dissociation inhibitor, D4-GDI, during apoptosis

Cited by 66 publications

References 30 publications

RhoGDI2 confers resistance to 5-fluorouracil in human gastric cancer cells

RhoGDI2 confers resistance to 5-fluorouracil in human gastric cancer cells

The caspase 6 derived N-terminal fragment of DJ-1 promotes apoptosis via increased ROS production

The Novel Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) Potently Enhances Apoptosis Induced by Tumor Necrosis Factor in Human Leukemia Cells

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