Hines Veterans Affairs Medical Center

Chicago, IL, United States

Hines Veterans Affairs Medical Center

Chicago, IL, United States
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Sondarva G.,Loyola University Chicago | Kundu C.N.,Texas A&M University | Mehrotra S.,Loyola University Chicago | Mishra R.,Loyola University Chicago | And 8 more authors.
Cell Research | Year: 2010

Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase that is activated by tumor necrosis factor-α (TNF-α) and specifically activates c-Jun N-terminal kinase (JNK) on TNF-α stimulation. The mechanism by which TNF-α activates MLK3 is still not known. TNF receptor-associated factors (TRAFs) are adapter molecules that are recruited to cytoplasmic end of TNF receptor and mediate the downstream signaling, including activation of JNK. Here, we report that MLK3 associates with TRAF2, TRAF5 and TRAF6; however only TRAF2 can significantly induce the kinase activity of MLK3. The interaction domain of TRAF2 maps to the TRAF domain and for MLK3 to its C-terminal half (amino acids 511-847). Endogenous TRAF2 and MLK3 associate with each other in response to TNF-α treatment in a time-dependent manner. The association between MLK3 and TRAF2 mediates MLK3 activation and competition with the TRAF2 deletion mutant that binds to MLK3 attenuates MLK3 kinase activity in a dose-dependent manner, on TNF-α treatment. Furthermore the downstream target of MLK3, JNK was activated by TNF-α in a TRAF2-dependent manner. Hence, our data show that the direct interaction between TRAF2 and MLK3 is required for TNF-α-induced activation of MLK3 and its downstream target, JNK. © 2010 IBCB, SIBS, CAS All rights reserved.


Hoenig H.,Duke University | Hoenig H.,Durham Medical Center | Griffiths P.,Emory University | Ganesh S.,Hines Veterans Affairs Medical Center | And 2 more authors.
American Journal of Physical Medicine and Rehabilitation | Year: 2012

OBJECTIVE: This study examined the accuracy of new wheelchair user predictions about their future wheelchair use. DESIGN: This was a prospective cohort study of 84 community-dwelling veterans provided a new manual wheelchair. RESULTS: The association between predicted and actual wheelchair use was strong at 3 mos (φ coefficient = 0.56), with 90% of those who anticipated using the wheelchair at 3 mos still using it (i.e., positive predictive value = 0.96) and 60% of those who anticipated not using it indeed no longer using the wheelchair (i.e., negative predictive value = 0.60, overall accuracy = 0.92). Predictive accuracy diminished over time, with overall accuracy declining from 0.92 at 3 mos to 0.66 at 6 mos. At all time points, and for all types of use, patients better predicted use as opposed to disuse, with correspondingly higher positive than negative predictive values. Accuracy of prediction of use in specific indoor and outdoor locations varied according to location. CONCLUSIONS: This study demonstrates the importance of better understanding the potential mismatch between the anticipated and actual patterns of wheelchair use. The findings suggest that users can be relied upon to accurately predict their basic wheelchair-related needs in the short-term. Further exploration is needed to identify characteristics that will aid users and their providers in more accurately predicting mobility needs for the long-term. Copyright © 2012 by Lippincott Williams & Wilkins.


Holgren C.,Hines Veterans Affairs Medical Center | Holgren C.,Loyola University Chicago | Dougherty U.,University of Chicago | Edwin F.,Loyola University Chicago | And 7 more authors.
Oncogene | Year: 2010

Sprouty negatively regulates receptor tyrosine kinase signals by inhibiting Ras/extracellular signal-regulated kinase (ERK) pathways. Sprouty is downregulated in breast, prostate and liver cancers and appears to function as a tumor suppressor. The role of sprouty in colonic neoplasia, however, has not been investigated. Sprouty-2 protein and mRNA transcripts were significantly upregulated in human colonic adenocarcinomas. Strikingly, the c-Met receptor was also upregulated in tumors with increased sprouty-2. To delineate a potential causal relationship between sprouty-2 and c-Met, K-ras mutant HCT-116 colon cancer cells were transduced with purified TAT-sprouty-2 protein or stably transfected with full-length human sprouty-2 gene. Sprouty-2 upregulation significantly increased cell proliferation by accelerating cell cycle transition. Sprouty-2 transfectants showed strong upregulation of c-Met protein and mRNA transcripts and hepatocyte growth factor-stimulated ERK and Akt phosphorylation and enhanced cell migration and invasion. In contrast, knockdown of c-Met by small interfering RNA (siRNA) significantly decreased cell proliferation, migration and invasion in sprouty-2 transfectants. Further, knockdown of sprouty-2 by siRNA in parental HT-29 and LS-174T colon cancer cells also decreased cell invasion. Sprouty-2 transfectants formed significantly larger tumor xenografts and showed increased proliferation and angiogenesis and suppressed apoptosis. Sprouty-2 tumors metastasized to the liver from cecal orthotopic implants, suggesting that sprouty-2 might also enhance metastatic signals. Thus, in colon cancer sprouty functions as an oncogene and its effects are mediated in part by c-Met upregulation. © 2010 Macmillan Publishers Limited All rights reserved.


Jin H.,Iowa State University | Kanthasamy A.,Iowa State University | Harischandra D.S.,Iowa State University | Kondru N.,Iowa State University | And 6 more authors.
Journal of Biological Chemistry | Year: 2014

The oxidative stress-sensitive protein kinase Cδ (PKCδ) has been implicated in dopaminergic neuronal cell death. However, little is known about the epigenetic mechanisms regulating PKCδ expression in neurons. Here, we report a novel mechanism by which the PKCδ gene can be regulated by histone acetylation. Treatment with histone deacetylase (HDAC) inhibitor sodium butyrate (NaBu) induced PKCδ expression in cultured neurons, brain slices, and animal models. Several other HDAC inhibitors also mimicked NaBu. The chromatin immunoprecipitation analysis revealed that hyperacetylation of histone H4 by NaBu is associated with the PKCδ promoter. Deletion analysis of the PKCδ promoter mapped the NaBu-responsive element to an 81-bp minimal promoter region. Detailed mutagenesis studies within this region revealed that four GC boxes conferred hyperacetylation-induced PKCδ promoter activation. Cotransfection experiments and Sp inhibitor studies demonstrated that Sp1, Sp3, and Sp4 regulated NaBu-induced PKCδ up-regulation. However, NaBu did not alter the DNA binding activities of Sp proteins or their expression. Interestingly, a one-hybrid analysis revealed that NaBu enhanced transcriptional activity of Sp1/Sp3. Overexpression of the p300/cAMP-response element-binding protein-binding protein (CBP) potentiated the NaBu-mediated transactivation potential of Sp1/Sp3, but expressing several HDACs attenuated this effect, suggesting that p300/CBP and HDACs act as coactivators or corepressors in histone acetylation-induced PKCδ up-regulation. Finally, using genetic and pharmacological approaches, we showed that NaBu up-regulation of PKCδ sensitizes neurons to cell death in a human dopaminergic cell model and brain slice cultures. Together, these results indicate that histone acetylation regulates PKCδ expression to augment nigrostriatal dopaminergic cell death, which could contribute to the progressive neuropathogenesis of Parkinson disease. © 2014, American Society for Biochemistry and Molecular Biology Inc. All rights reserved.


Ghosh A.,Iowa State University | Saminathan H.,Iowa State University | Kanthasamy A.,Iowa State University | Anantharam V.,Iowa State University | And 7 more authors.
Journal of Biological Chemistry | Year: 2013

Background: Pin1 regulates several signaling proteins by isomerizing the cis/trans conformation of the Ser(P)-Pro peptide bond. Results: Pin1 is up-regulated in dopaminergic neurons in cell culture, animal models, and human PD brains. Pin1 inhibition protects dopaminergic neurons in PD models. Conclusion: Pin1 up-regulation plays a proapoptotic function in PD. Significance: Pin1 inhibition may be a viable translational strategy in PD. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.


Rana A.,Loyola University Chicago | Rana A.,Hines Veterans Affairs Medical Center | Rana B.,Hines Veterans Affairs Medical Center | Rana B.,Loyola University Chicago | And 8 more authors.
Genes and Cancer | Year: 2013

Mixed lineage kinases (MLKs) are members of the mitogen-activated protein kinase kinase kinase (MAP3K) family and are reported to activate MAP kinase pathways. There have been at least 9 members of the MLK family identified to date, although the physiological functions of all the family members are yet unknown. However, MLKs in general have been implicated in neurodegenerative diseases, including Parkinson and Alzheimer diseases. Recent reports suggest that some of the MLK members could play a role in cancer via modulating cell migration, invasion, cell cycle, and apoptosis. This review article will first describe the biology of MLK members and then discuss the current progress that relates to their functions in cancer. © The Author(s) 2013.


Rangasamy V.,Loyola University Chicago | Mishra R.,Loyola University Chicago | Mehrotra S.,Loyola University Chicago | Sondarva G.,Loyola University Chicago | And 7 more authors.
Cancer Research | Year: 2010

Little knowledge exists about the mechanisms by which estrogen can impede chemotherapy-induced cell death of breast cancer cells. 17β-Estradiol (E2) hinders cytotoxic drug-induced cell death in estrogen receptor-positive (ER+) breast cancer cells. We noted that the activity of the proapoptotic mixed lineage kinase 3 (MLK3) kinase was relatively higher in estrogen receptor-negative (ER-) breast tumors, suggesting that E2 might inhibit MLK3 activity. The kinase activities of MLK3 and its downstream target, c-Jun NH2-terminal kinase, were rapidly inhibited by E2 in ER+ but not in ER- cells. Specific knockdown of AKT1/2 prevented MLK3 inhibition by E2, indicating that AKT mediated this event. Furthermore, MLK3 inhibition by E 2 involved phosphorylation of MLK3 Ser674 by AKT, attenuating the proapoptotic function of MLK3. We found that a pan-MLK inhibitor (CEP-11004) limited Taxol-induced cell death and that E2 accentuated this limitation. Taken together, our findings indicate that E2 inhibits the proapoptotic function of MLK3 as a mechanism to limit cytotoxic drug-induced death of ER+ breast cancer cells. ©2010 AACR.


Mishra P.,Loyola University Chicago | Senthivinayagam S.,Loyola University Chicago | Rangasamy V.,Loyola University Chicago | Sondarva G.,Loyola University Chicago | And 2 more authors.
Molecular Endocrinology | Year: 2010

Gastrin is a gastrointestinal peptide hormone, secreted by the gastric G cells and can exist as a fully processed amidated form (G17) or as unprocessed forms. All forms of gastrin possess trophic properties towards the gastrointestinal mucosa. An understanding of the signaling pathways involved is important to design therapeutic approaches to target gastrin-mediated cellular events. The studies described here were designed to identify the signaling pathways by which amidated gastrin (G17) mediates cancer cell migration. These studies indicated a time- and dose-dependent increase in gastric cancer cell migration after G17 stimulation, involving cholecystokinin 2 receptor. G17-induced migration was preceded by activation of MAPK pathways and was antagonized after pretreatment with SP600125, a pharmacological inhibitor of c-Jun-NH2-terminal kinase (JNK) pathway. Knockdown of endogenous JNK1 expression via small interference RNA (JNK1-siRNA) inhibited G17-induced phosphorylation of c-Jun and migration, and overexpression of wild-type JNK1 or constitutive active JNK1 promoted G17-induced migration. Studies designed to identify the MAPK kinase kinase member mediating JNK activation indicated the involvement of mixed lineage kinase-3 (MLK3), which was transiently activated upon G17 treatment. Inhibition of MLK3 pathway via a pan-MLK inhibitor or knockdown of MLK3 expression by MLK3-siRNA antagonized G17-induced migration. Incubation with G17 also resulted in an induction of matrix metalloproteinase 7 promoter activity, which is known to mediate migration and invasion pathways in cancer cells. Modulation of MLK3, JNK1, and c-Jun pathways modulated G17-induced matrix metalloproteinase 7 promoter activation. These studies indicate that the MLK3/JNK1 axis mediates G17-induced gastric cancer cell migration, which can be targeted for designing novel therapeutic strategies for treating gastric malignancies. Copyright © 2010 by The Endocrine Society.


Khare S.,Hines Veterans Affairs Medical Center | Khare S.,Loyola University Chicago | Verma M.,U.S. National Institutes of Health
Methods in Molecular Biology | Year: 2012

Accumulation of genetic and epigenetic alterations transforms normal colonic epithelial cells to adenocarcinoma cells. Genetic alterations include mutations in tumor suppressor genes and oncogenes, whereas epigenetic mechanisms are defined as heritable alterations in gene expression that is independent of changes in the primary DNA sequence. Role of epigenetic mechanisms in development and maintenance of organ- and tissue-specific gene expression is now realized. Disturbances in epigenetic landscape can lead to malignant cellular makeover, and these heritable changes are maintained through various cycles of cell division that renders cells to have discrete identity with similar genetic information. Epigenetic alterations in colorectal cancer (CRC) that transform colonic epithelial cells into adenocarcinoma cells include aberrant DNA methylation, chromatin modifications, and noncoding RNAs, especially microRNA expression. CpG island DNA methylation and aberrant methylation of genes drive the initiation and progression of CRC. Histone modifications impinge on chromatin structure and gene expression and thus play an important role in gene silencing in CRC. DNA hypermethylation also leads to downregulation and inappropriate expression of certain microRNAs that act like tumor suppressor genes. Determining the causes and roles of epigenetic instability in CRC pathogenesis will lead to effective prevention and therapeutic strategies for patients with CRC. Epigenetic drugs that underscore the reversible nature of epigenetic events have led the possibility of epigenetic therapy as a treatment option in CRC. © 2012 Springer Science+Business Media, LLC.


PubMed | Hines Veterans Affairs Medical Center
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2012

Accumulation of genetic and epigenetic alterations transforms normal colonic epithelial cells to adenocarcinoma cells. Genetic alterations include mutations in tumor suppressor genes and oncogenes, whereas epigenetic mechanisms are defined as heritable alterations in gene expression that is independent of changes in the primary DNA sequence. Role of epigenetic mechanisms in development and maintenance of organ- and tissue-specific gene expression is now realized. Disturbances in epigenetic landscape can lead to malignant cellular makeover, and these heritable changes are maintained through various cycles of cell division that renders cells to have discrete identity with similar genetic information. Epigenetic alterations in colorectal cancer (CRC) that transform colonic epithelial cells into adenocarcinoma cells include aberrant DNA methylation, chromatin modifications, and noncoding RNAs, especially microRNA expression. CpG island DNA methylation and aberrant methylation of genes drive the initiation and progression of CRC. Histone modifications impinge on chromatin structure and gene expression and thus play an important role in gene silencing in CRC. DNA hypermethylation also leads to downregulation and inappropriate expression of certain microRNAs that act like tumor suppressor genes. Determining the causes and roles of epigenetic instability in CRC pathogenesis will lead to effective prevention and therapeutic strategies for patients with CRC. Epigenetic drugs that underscore the reversible nature of epigenetic events have led the possibility of epigenetic therapy as a treatment option in CRC.

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