| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, and
Department of Research, Introgen Therapeutics Inc., Houston, TX 77030; and
Corixa Corp., Seattle, WA 98104
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, and IFN-
and low levels of IL-1
, IL-12, and GM-CSF from
human PBMC as measured by ELISA. The MDA-7/IL-24-mediated induction of
these Th1-type cytokines was inhibited by the addition of IL-10 to the
PBMC cultures, suggesting that these two related protein family members
may provide antagonistic functions. Therefore, because human blood
leukocytes can be stimulated to produce MDA-7/IL-24, as well as respond
to MDA-7/IL-24 by expressing secondary cytokines, MDA-7/IL-24 has the
expression profile and major functional attributes that justify its
designation as an IL. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, TNF-, and IL-6 (3). Multiple
cellular and viral homologs of IL-10 have been identified
(4, 5, 6, 7, 8, 9, 10), and several cellular members (IL-10, IL-19,
IL-20, melanoma differentiation-associated gene 7
(MDA-7)4/IL-24) of the
IL-10 cytokine family are encoded in a small 195-kb gene cluster on
chromosome 1q32, and have structural and sequence homologies (6, 7, 11). The MDA-7 IL-10 family member has been characterized
primarily by its tumor suppressor activity. MDA-7 was identified and
cloned using the differentiation induction subtraction hybridization
approach after treatment of the human HO-1 melanoma cell line with
IFN- and mezerein resulted in growth arrest and terminal
differentiation (10). Overexpression of MDA-7 via
adenoviral vector (Ad-MDA7) infection induces apoptosis of a number of
tumor cell types, but not normal cells, and in model tumor systems has
led to suppressed growth and reduced metastasis (12, 13, 14, 15, 16).
Apoptotic proteins up-regulated or activated by Ad-MDA7 include p53,
caspases, Bax, and Bak (15), and attempts for its use in
human cancer gene therapy are underway.
Several features of MDA-7 suggest that it may be a member of the IL
family; these features include chromosomal location, translational
regulation, murine and rat homolog expression, and putative protein
structure (11, 17, 18, 19). Similar to GM-CSF, TNF-, and
IFN- transcripts, all of which contain AU-rich elements in their 3'
untranslated region targeting mRNA for rapid degradation, MDA-7 has
three AU-rich elements in its 3' untranslated region (17).
MDA-7 mRNA has been identified in human PBMC (11)
and, although no cytokine function of human MDA-7 has been
previously reported, MDA-7 has been designated as IL-24 based on the
gene and protein sequence characteristics (National Center for
Biotechnology Information database accession no. XM_001405) and
will be referred to as MDA-7/IL-24. The murine MDA-7/IL-24 homolog
IL-4-induced secreted protein (FISP) was reported as a Th2-specific
cytokine (18). Transcription of FISP is induced by TCR and
IL-4R engagement and subsequent protein kinase C and STAT6
activation, as demonstrated by knockout studies. Expression of FISP was
characterized, but no function has yet been attributed to this putative
cytokine (18). The rat MDA-7/IL-24 homolog C49a (Mob-5) is
78% homologous to the MDA-7/IL-24 gene and has been implicated in
wound healing (19, 20). Mob-5 was also shown to be a
secreted protein and a putative cell surface receptor was identified on
ras-transformed cells (20). Therefore, homologs
of the MDA-7/IL-24 are expressed and secreted in various species,
further supporting the cytokine-like nature of this molecule.
We now present data that define human MDA-7/IL-24 as a functional cytokine; we demonstrate its expression in human PBMC and its ability to induce Th1 type cytokine secretion from human PBMC. MDA-7/IL-24 stimulation of PBMC resulted in cytokine production that was antagonized by IL-10, suggesting that the balance of these two similar molecules may provide a previously unrecognized homeostasis of the immune system. To our knowledge, this is the first report of a tumor suppressor for which the protein product can also be secreted and function as a cytokine.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
PBMC were isolated from the peripheral blood of normal healthy
donors by centrifugation over Histopaque (Sigma-Aldrich, St. Louis,
MO). Cells were cultured in AIMV (see Figs. 1
, 4, and 5) or in RPMI
1640-based medium (see Fig. 2) supplemented with
L-glutamine, HEPES, penicillin, streptomycin, and 10%
human AB serum (Pelfreez, Brown Deer, WI). Both PHA-P and LPS were
purchased from Sigma-Aldrich. Four hours before harvest of cells
for the Western blot and immunohistochemistry, brefeldin A
(Sigma-Aldrich) was added at a final concentration of 10 µg/ml.
|
|
|
|
Immunohistochemical staining for MDA-7/IL-24
Immunostaining of human PBMC or subclasses was performed using a mouse mAb against human MDA-7/IL-24 (Introgen Therapeutics, Houston, TX), using an avidin-biotinylated-peroxidase complex method optimized by us previously for melanocytes and melanoma cells (21). Specificity of the anti-MDA-7/IL-24 Ab was confirmed by total blocking with recombinant MDA-7/IL-24 produced in Escherichia coli, as previously published (21).
ELISAs. The ELISA reaction to detect human MDA-7/IL-24 was conducted in 96-well plates using standard techniques and an Ab pair selected for sensitivity. Briefly, plates were coated with a mAb (I) against MDA-7/IL-24 (prepared and provided by Introgen Therapeutics) overnight at 4°C in a standard sodium carbonate coating buffer. The plate was blocked for 2 h at room temperature with blocking buffer composed of PBS containing BSA and 1% thimerosal. Protein samples or recombinant MDA-7/IL-24 produced and purified from E. coli were diluted in diluent buffer (blocking buffer with Tween 20 added at a final concentration of 1%) and incubated with the Ab for 2 h at room temperature in the presence of 2% nonfat dry milk in diluent. After extensive washing with 0.1% Tween 20 in PBS, a biotinylated mAb (II) against MDA-7/IL-24 was added to the plate and incubated for 1 h at room temperature. After washing, HRP-streptavidin (Southern Biotechnology Associates, Birmingham, AL) was added to the plate for 30 min at room temperature. The reaction was developed with the addition of TMB microwell peroxidase substrate (Kirkegaard & Perry Laboratories, Gaithersburg, MD) and stopped with 1 N H2SO4 after 10 min. The ODs were recorded in a microtiter plate reader at a 450-nm wavelength (Dynatech, Chantilly, VA). ELISA for other cytokines were performed with commercially available kits according to the manufacturers’ instructions as designated in the figures. Although multiple experiments were performed, each was performed in duplicate as indicated by the manufacturer, so statistical errors for each value is not possible.
Western blotting. Activated PBMC were washed once in 1x PBS, resuspended in modified RIPA buffer (TBS (pH 7.6), 1% Nonidet P-40, 0.5% sodium deoxycholate, 0.1% SDS, 50 mM sodium fluoride, 0.2 mM aprotinin, and 1 mM leupeptin) and rocked at 4°C for 20 min. Lysates were cleared by a 30-min centrifugation at 16,000 x g at 4°C. Protein concentrations were determined with the DC Protein Assay (Bio-Rad, Hercules, CA) and samples were boiled for 5 min in an equal volume of sample buffer (62.5 mM Tris-HCl (pH 6.8), 20% glycerol, 2% SDS, and 5% 2-ME). Samples were separated by SDS-PAGE on a 12% gel and transferred to nitrocellulose. The membrane was blocked for 30 min with blocking buffer (5% milk in 1x PBS, 0.1% Tween 20 (PBST)) and incubated in a rabbit polyclonal MDA-7/IL-24 Ab (Introgen Therapeutics) in blocking buffer. Subsequently the membranes were washed twice in PBST and incubated at 1/2,000 with HRP-conjugated goat anti-rabbit secondary Ab. Blots were developed with ECL reagent (Amersham Pharmacia Biotech, Piscataway, NJ). Membranes were incubated in stripping buffer (62.5 mM Tris-HCl (pH 6.7), 2% SDS, and 100 mM 2-ME) for 30 min at 60°C, washed three times with PBST for 10 min each, and reprobed with anti-actin Ab (1/1,000).
Purification of human MDA-7/IL-24
The full-length cDNA of MDA-7/IL-24 was cloned into the pCEP4
FLAG vector (Invitrogen, San Diego, CA) containing the CMV promoter.
The plasmid was transfected into HEK 293 cells and stable subclones
were isolated using hygromycin (0.4 µg/ml). Purification of
MDA-7/IL-24 was performed using the HEK 293 cell supernatants collected
from viable cells in log phase growth. The crude supernatant was
determined by ELISA to contain 
30 ng/ml MDA-7/IL-24. Supernatant
containing the secreted MDA-7/IL-24 was supplemented with protease
inhibitors (1 µg/ml leupeptin, 1 µg/ml pepstatin, and 0.5 mM PMSF)
and 0.05% sodium azide and was concentrated 10-fold with an Amicon
stirred cell (Amicon, Beverly, MA) on a YM10 membrane. No detectable
actin was in these supernatants, supporting the assumption that it was
not derived from dead cells. Ten-milliliter aliquots of concentrated
supernatant were separated over an S200 Superdex prep grade column
(Amersham Pharmacia, Piscataway, NJ) in 1x PBS (pH 7.4), and
fractions identified to contain MDA-7/IL-24 by Western blot and ELISA
were pooled. After buffer exchange on an Amicon stirred cell to 50 mM
MES (pH 6), a second purification step was performed using a Bio-Rad S
column. Column conditions consisted of a 0- to 90-mM NaCl gradient, a
5-min hold at 90 mM NaCl, a 30-min 90- to 250-mM gradient at 1 ml/min,
and a 5-min hold at 250 mM NaCl. The entire purification was conducted
at 4°C and MDA-7/IL-24 was identified using ELISA and Western
blotting procedures. The final samples contained at least 300 ng/ml
MDA-7 as determined by ELISA, and the specific activity was enriched at
least 28-fold over the starting supernatant material based on the
elimination of extraneous protein. Individual lots of partially
purified MDA-7/IL-24 were tested for endotoxin using the QCL 1000
quantitative chromogenic LAL kit (BioWhittaker, Walkersville, MD).
Levels of endotoxin ranged from 0 to 10 EU/ml.
Analysis of the protein structure as well as the hydrophobicity was performed by analyzing the amino acid sequence using the ProtParam tool, ExPASy server (us.expasy.org). Hydrophobicity was assessed using the Kyte and Dolittle scale provided by this site, applying the linear weight variation model.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Fresh normal donor human PBMC were either unactivated or treated
with the polyclonal stimuli of PHA or LPS, and were examined for
intracellular MDA-7/IL-24 expression by immunoblotting and
immunohistochemistry. As shown in Fig. 1
, untreated PBMC do not express detectable levels of MDA-7/IL-24.
However, after treatment with PHA or LPS for 72 h, MDA-7/IL-24
with an observed molecular mass of 23 kDa was evident. Two of four
other donors tested had a detectable level of MDA-7/IL-24 upon PHA and
LPS stimulation, and one of the three donors had a very low amount of
MDA-7/IL-24 in cultured unactivated PBMC (data not shown). The levels
of MDA-7/IL-24 may be at the threshold of sensitivity of our Ab and
blotting procedure; therefore, MDA-7/IL-24 may not be detected in the
donors that are just below the threshold. These results correlate with
a recent report of the detection of MDA-7/IL-24 mRNA in the thymus,
spleen, and PBL (11) as well as MDA-7/IL-24 secretion from
Con A-treated PBMC (22).
MDA-7 is expressed by non-CD3 subsets
To determine which subclasses of PHA-stimulated PBMC express
MDA-7/IL-24, subtypes were analyzed by immunohistochemistry. Positively
selected CD3+ T cells (six of six experiments,
Fig. 2a) and monocytes (three
of three experiments, Fig. 2d) were routinely negative for
MDA-7/IL-24, but 15–20% of the CD19+ (three of
three experiments, Fig. 2b) and 50–80% of the
CD56+ (three of three experiments, Fig. 2c) subpopulations resulting from the same starting PBMC and
separation procedures were unequivocally positive. Membrane staining of
MDA-7/IL-24 was most evident in the CD56+ cells,
and a granular location in both B cells and NK cells was observed.
MDA-7 can be a secreted protein
One of the characteristics of a cytokine is the ability to be
secreted. Usually, a short stretch of hydrophobic amino acids at the
amino terminus signals and targets the protein to a secretory pathway.
As shown in Fig. 3a, the
MDA-7/IL-24 contains a leader sequence consisting of 49 amino acids;
this is depicted in more detail in the hydrophobicity plot (Fig. 3c). The predicted cleavage site was determined by the von
Heijne SignalP predictions program (23); however, this
cleavage site in MDA-7/IL-24 has not been confirmed experimentally. To
demonstrate secretion of MDA-7/IL-24 from mammalian cells, stable
transfectants of HEK 293 cells containing the human full-length
MDA-7/IL-24 cDNA were generated. Supernatants were analyzed for the
presence of MDA-7/IL-24 by Western blot (Fig. 3b) and four
bands of MDA-7/IL-24 were detected in the culture supernatants of
MDA-7/IL-24 transfected but not untransfected HEK 293 cells. Based on
the amino acid sequence, the full-length MDA-7/IL-24 is expected to
have a molecular mass of 23,824 Da, and the final secreted peptide is
18,419 Da.
|
Another hallmark of the cytokine family is belonging to a cascade
of molecules involved in cellular activation or inhibition. To address
the biological function of MDA-7/IL-24 as a cytokine, its induction of
secondary cytokine secretion by PBMC was examined. Preliminary
experiments using recombinant MDA-7/IL-24, expressed in E.
coli and Saccharomyces cerevisiae, showed that MDA-7
could induce robust production of IL-6, TNF-, and IFN-, very low
levels of GM-CSF and IL-10, and no IL-2, IL-4, and IL-5 (data not
shown). However, very high doses (quantities measured in micrograms per
milliliter) of bacterial MDA-7/IL-24 were required to stimulate a
response, possibly due to improper folding or lack of glycosylation of
the recombinant protein. Therefore, secreted MDA-7/IL-24 was purified
from supernatants of HEK 293 cells (MDA-7/IL-24 expressing stable
transfectants) and used to test the effect of MDA-7/IL-24 on human
PBMC.
Optimum levels of MDA-7/IL-24 to induce maximal IL-6, TNF-, and
IFN- secretion were determined in a dose-response curve. Maximal
IL-6 secretion was achieved by only 2 ng/ml MDA-7/IL-24, while maximal
TNF- and IFN- secretion required 20 ng/ml MDA-7/IL-24 (data not
shown). High levels of IL-6, TNF-, and IFN- were secreted by PBMC
in response to MDA-7/IL-24 in the representative donor shown in Fig. 4. In fact, MDA-7/IL-24 was a more potent
inducer of TNF- than LPS, a known inducer of inflammatory cytokines
that was used as a positive control. All donors tested secreted IL-6,
TNF-, and IFN- in response to MDA-7/IL-24; some cytokine levels
were higher and some were lower than the donor in Fig. 4. PHA, another
positive control, always induced robust cytokine secretion from all
donors and untransfected 293 supernatants did not induce any
significant levels of cytokines (data not shown). A similar pattern of
MDA-7/IL-24 stimulation of cytokine production, albeit much lower
levels, was observed with IL-1, IL-12, and GM-CSF as shown in Fig. 5. Values in a similar range of the
amount of cytokines from the donor shown in Fig. 5 were detected in
supernatants from three additional donors. Using polyclonal antisera
specific for MDA-7/IL-24, depletion of the MDA-7/IL-24 by >90%, as
determined by ELISA, resulted in significant reduction of induction of
IFN- secretion (data not shown), indicating that the induction of
these secondary cytokines was MDA-7/IL-24 specific.
As the IL-10 family member MDA-7/IL-24 stimulates the production of
proinflammatory cytokines, we hypothesized that MDA-7/IL-24 and IL-10,
a potent immunosuppressive cytokine, may be antagonists. To test this
hypothesis, human rIL-10 and human recombinant MDA-7/IL-24 were
added to the PBMC cultures at the same time. Under the conditions used,
IL-10 completely abrogated TNF-, IFN-, IL-12, and GMCSF induction
by MDA-7/IL-24 and partially blocked IL-6 and IL-1 induction by
MDA-7/IL-24 (Figs. 4 and 5). As a positive control, IL-10
coadministration also reduced or completely blocked the production of
all cytokines, except IL-6, in response to LPS. The lack of inhibition
of LPS-induced IL-6 secretion by IL-10 is probably due to the extremely
potent stimulatory activity of LPS and the IL-6 values being above the
standard curve of the ELISA for IL-10 untreated and treated samples. As
is the case with any study using freshly isolated human PBMC there was
some variability from donor to donor, but the induction of secondary
cytokines by MDA-7/IL-24 and inhibition by IL-10 were consistent in all
donors tested and all experiments.
MDA-7 does not appear to function as a growth factor for human PBMC
Because some cytokines can also function as growth factors, the
ability of MDA-7/IL-24 to act as a proliferative stimulus was addressed
using human PBMC and the results are reported
in Table I. IL-10 was included as a
negative cytokine control. PHA was used as positive control and induced
a robust uptake of [3H]thymidine in all three
donors tested. As expected, IL-10 did not induce increased
[3H]thymidine uptake of PBMC over the course of
4 days. Our results show that MDA-7/IL-24, purified from HEK 293
supernatants, did not induce significant proliferation during 4 days of
culture of the PBMC population in any of the three donors tested.
Earlier studies using recombinant MDA-7/IL-24 (up to 5 µg/ml)
expressed in E. coli or S. cerevisiae also did
not show a proliferative response in human PBMC from three donors (data
not shown).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Activation of immune cells in vitro with PHA or LPS or in vivo with a
microbial infection results in transcription, translation, and
secretion of cytokines, including MDA-7/IL-24, as indicated by our in
vitro studies using human PBMC. These cytokines can then act locally or
systemically to initiate further cytokine cascades that are critical to
the regulation of effective immunity. Because immune cells have been
demonstrated to respond to MDA-7/IL-24 by secretion of cytokines, it
can be hypothesized that these cells must express an MDA-7/IL-24
receptor. The MDA-7/IL-24 receptor has recently been identified and
uses one of the IL-10R subunits (22, 24), similar to
another IL-10 homolog, IL-22, which uses the IL-10R chain in
addition to its own unique chain (25). In fact,
MDA-7/IL-24 can bind the IL-22R (IL-22R1/IL-20R2) and the IL-20R
(IL-20R1/IL-20R1) (22) and induce STAT3 phosphorylation
(24). Because IL-10 and MDA-7 share a receptor subunit,
the mechanism of IL-10 inhibition of MDA-7/IL-24-induced cytokine
secretion may be due to the 10-fold higher affinity of IL-10 for its
receptor (22), in addition to a potential interference of
MDA-7/IL-24 signal transduction and inhibition of TNF-, IFN-,
IL-6, IL-1, IL-12, and GM-CSF transcription or translation (1, 3).
Whether MDA-7/IL-24 can directly induce transcription and/or secretion
of all of these cytokines or induces only one or two, which can then
induce the remaining cytokines, awaits dissection with various
combinations of blocking Abs. For example, indirect stimulation may be
the case with IFN-, as only very low levels were observed at 36
h in three of four donors (data not shown) but higher levels were
detected by 48 h. A full kinetic analysis of secondary cytokine
expression is now warranted to resolve these questions.
It has not been established whether MDA-7/IL-24 exists and functions as
a homodimer like IL-10, or whether it may form a heterodimer with IL-10
or another protein, or possibly can form multimeric associations. The
multiple bands observed in the Western blots of 293 supernatants are
most likely due to posttranslational modification such as glycosylation
(22), because there are three predicted glycosylation
sites at positions 95, 109, and 126, as depicted in Fig. 3a.
Other cytokines have been demonstrated to be glycosylated to varying
degrees (26, 27). In Fig. 1 (cell lysate) the size of
MDA-7/IL-24 may be smaller than in the Western blot in Fig. 3b (supernatant), because the protein may not have been
fully glycosylated yet, as secretion had not occurred.
High expression of MDA-7/IL-24 has been detected previously in melanocytes by Western blot and immunohistochemistry (21). When comparing paired primary and metastatic melanomas, a significantly lower number and intensity of MDA-7/IL-24 staining was observed in metastatic tumors (21). In contrast, 10 of 12 primary lesions and six of seven metastatic tumors were positive for IL-10 by immunohistochemistry (2). We hypothesize that, based on the relative levels of MDA-7/IL-24 and IL-10, immune cells in proximity to the primary melanoma lesion could be either activated and secrete proinflammatory cytokines (if MDA-7/IL-24 predominates) or be suppressed (if IL-10 is present in excess). If the MDA-7/IL-24:IL-10 ratio were higher, some of these secondary cytokines could activate APCs that are presenting melanoma tumor Ags, thereby creating an antitumor immune response. Therefore, we hypothesize that loss of MDA-7/IL-24 in melanoma progression (17, 21), and thus the lack of expression of MDA-7/IL-24 in metastatic melanomas, together with high expression of the immunosuppressive cytokine IL-10 in melanoma, could contribute to the ineffective immune response to melanoma.
The interactions of MDA-7/IL-24 and IL-10 and the cytokines they induce or repress comprise a very complex network. We hypothesize that MDA-7/IL-24 loss plays a role in the tumorigenesis of melanoma and may have a dual function as tumor suppressor and cytokine. To date this molecule has been commonly called MDA-7; for future studies as a functional cytokine, the term IL-24 may be more appropriate when referring to the immune or IL-like properties associated with MDA-7.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 E.G.C. and J.B.M. contributed equally to the research presented in this manuscript.
3 Address correspondence and reprint requests to Dr. Elizabeth A. Grimm, Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Box 422, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail address: egrimm{at}mdanderson.org
4 Abbreviations used in this paper: MDA-7, melanoma differentiation-associated gene-7; FISP, IL-4-induced secreted protein.
Received for publication December 26, 2001. Accepted for publication April 17, 2002.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  K. L. Fuson, M. Zheng, M. Craxton, A. Pataer, R. Ramesh, S. Chada, and R. B. Sutton Structural Mapping of Post-translational Modifications in Human Interleukin-24: ROLE OF N-LINKED GLYCOSYLATION AND DISULFIDE BONDS IN SECRETION AND ACTIVITY J. Biol. Chem., October 30, 2009; 284(44): 30526 - 30533. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Andoh, M. Shioya, A. Nishida, S. Bamba, T. Tsujikawa, S. Kim-Mitsuyama, and Y. Fujiyama Expression of IL-24, an Activator of the JAK1/STAT3/SOCS3 Cascade, Is Enhanced in Inflammatory Bowel Disease J. Immunol., July 1, 2009; 183(1): 687 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Park, T. Walker, A. P. Martin, J. Allegood, N. Vozhilla, L. Emdad, D. Sarkar, M. Rahmani, M. Graf, A. Yacoub, et al. MDA-7/IL-24-induced cell killing in malignant renal carcinoma cells occurs by a ceramide/CD95/PERK-dependent mechanism Mol. Cancer Ther., May 1, 2009; 8(5): 1280 - 1291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sainz-Perez, H. Gary-Gouy, F. Gaudin, G. Maarof, A. Marfaing-Koka, T. de Revel, and A. Dalloul IL-24 Induces Apoptosis of Chronic Lymphocytic Leukemia B Cells Engaged into the Cell Cycle through Dephosphorylation of STAT3 and Stabilization of p53 Expression J. Immunol., November 1, 2008; 181(9): 6051 - 6060. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sahoo, Y. M. Jung, H.-K. Kwon, H.-J. Yi, S. Lee, S. Chang, Z.-Y. Park, K.-C. Hwang, and S.-H. Im A Novel Splicing Variant of Mouse Interleukin (IL)-24 Antagonizes IL-24-induced Apoptosis J. Biol. Chem., October 24, 2008; 283(43): 28860 - 28872. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Pataer, W. Hu, L. Xiaolin, S. Chada, J. A. Roth, K. K. Hunt, and S. G. Swisher Adenoviral endoplasmic reticulum-targeted mda-7/interleukin-24 vector enhances human cancer cell killing Mol. Cancer Ther., August 1, 2008; 7(8): 2528 - 2535. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sauane, Z.-z. Su, P. Gupta, I. V. Lebedeva, P. Dent, D. Sarkar, and P. B. Fisher Autocrine regulation of mda-7/IL-24 mediates cancer-specific apoptosis PNAS, July 15, 2008; 105(28): 9763 - 9768. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Luo, Q. Xia, R. Zhang, C. Lv, W. Zhang, Y. Wang, Q. Cui, L. Liu, R. Cai, and C. Qian Treatment of Cancer with a Novel Dual-Targeted Conditionally Replicative Adenovirus Armed with mda-7/IL-24 Gene Clin. Cancer Res., April 15, 2008; 14(8): 2450 - 2457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yacoub, M. A. Park, P. Gupta, M. Rahmani, G. Zhang, H. Hamed, D. Hanna, D. Sarkar, I. V. Lebedeva, L. Emdad, et al. Caspase-, cathepsin-, and PERK-dependent regulation of MDA-7/IL-24-induced cell killing in primary human glioma cells Mol. Cancer Ther., February 1, 2008; 7(2): 297 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yacoub, P. Gupta, M. A. Park, M. Rhamani, H. Hamed, D. Hanna, G. Zhang, D. Sarkar, I. V. Lebedeva, L. Emdad, et al. Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling Mol. Cancer Ther., February 1, 2008; 7(2): 314 - 329. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Wu, C. Huang, L. Garcia, A. P. de Leon, J. S. Osornio, M. Bobadilla-del-Valle, L. Ferreira, S. Canizales, P. Small, M. Kato-Maeda, et al. Unique Gene Expression Profiles in Infants Vaccinated with Different Strains of Mycobacterium bovis Bacille Calmette-Guerin Infect. Immun., July 1, 2007; 75(7): 3658 - 3664. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Sarkar, I. V. Lebedeva, Z.-z. Su, E.-S. Park, L. Chatman, N. Vozhilla, P. Dent, D. T. Curiel, and P. B. Fisher Eradication of Therapy-Resistant Human Prostate Tumors Using a Cancer Terminator Virus Cancer Res., June 1, 2007; 67(11): 5434 - 5442. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sauane, P. Gupta, I. V. Lebedeva, Z.-z. Su, D. Sarkar, A. Randolph, K. Valerie, R. V. Gopalkrishnan, and P. B. Fisher N-Glycosylation of MDA-7/IL-24 Is Dispensable for Tumor Cell-Specific Apoptosis and "Bystander" Antitumor Activity Cancer Res., December 15, 2006; 66(24): 11869 - 11877. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Garcia, J. Gil, I. Ventoso, S. Guerra, E. Domingo, C. Rivas, and M. Esteban Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative Action Microbiol. Mol. Biol. Rev., December 1, 2006; 70(4): 1032 - 1060. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Kokkinakis, A. G. Brickner, J. M. Kirkwood, X. Liu, J. E. Goldwasser, A. Kastrama, C. Sander, D. Bocangel, and S. Chada Mitotic Arrest, Apoptosis, and Sensitization to Chemotherapy of Melanomas by Methionine Deprivation Stress Mol. Cancer Res., August 1, 2006; 4(8): 575 - 589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. V. Lebedeva, D. Sarkar, Z.-Z. Su, R. V. Gopalkrishnan, M. Athar, A. Randolph, K. Valerie, P. Dent, and P. B. Fisher Molecular Target-Based Therapy of Pancreatic Cancer Cancer Res., February 15, 2006; 66(4): 2403 - 2413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. B. Fisher Is mda-7/IL-24 a "Magic Bullet" for Cancer? Cancer Res., November 15, 2005; 65(22): 10128 - 10138. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sarkar, Z.-z. Su, N. Vozhilla, E. S. Park, P. Gupta, and P. B. Fisher Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice PNAS, September 27, 2005; 102(39): 14034 - 14039. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. J. Poindexter, E. T. Walch, S. Chada, and E. A. Grimm Cytokine induction of interleukin-24 in human peripheral blood mononuclear cells J. Leukoc. Biol., September 1, 2005; 78(3): 745 - 752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Oida, B. Gopalan, R. Miyahara, S. Inoue, C. D. Branch, A. M. Mhashilkar, E. Lin, B. N. Bekele, J. A. Roth, S. Chada, et al. Sulindac enhances adenoviral vector expressing mda-7/IL-24-mediated apoptosis in human lung cancer Mol. Cancer Ther., February 1, 2005; 4(2): 291 - 304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Kokkinakis, X. Liu, S. Chada, M. M. Ahmed, M. M. Shareef, U. K. Singha, S. Yang, and J. Luo Modulation of Gene Expression in Human Central Nervous System Tumors under Methionine Deprivation-induced Stress Cancer Res., October 15, 2004; 64(20): 7513 - 7525. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Aggarwal, Y. Takada, A. M. Mhashilkar, K. Sieger, S. Chada, and B. B. Aggarwal Melanoma Differentiation-Associated Gene-7/IL-24 Gene Enhances NF-{kappa}B Activation and Suppresses Apoptosis Induced by TNF J. Immunol., October 1, 2004; 173(7): 4368 - 4376. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. W. Bartlett, L. Dumoutier, J.-C. Renauld, S. V. Kotenko, C. E. McVey, H.-J. Lee, and G. L. Smith A new member of the interleukin 10-related cytokine family encoded by a poxvirus J. Gen. Virol., June 1, 2004; 85(6): 1401 - 1412. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Ramesh, A. M. Mhashilkar, F. Tanaka, Y. Saito, C. D. Branch, K. Sieger, J. B. Mumm, A. L. Stewart, A. Boquio, L. Dumoutier, et al. Melanoma Differentiation-associated Gene 7/Interleukin (IL)-24 Is a Novel Ligand That Regulates Angiogenesis via the IL-22 Receptor Cancer Res., August 15, 2003; 63(16): 5105 - 5113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yacoub, C. Mitchell, A. Lister, I. V. Lebedeva, D. Sarkar, Z.-Z. Su, C. Sigmon, R. McKinstry, V. Ramakrishnan, L. Qiao, et al. Melanoma Differentiation-associated 7 (Interleukin 24) Inhibits Growth and Enhances Radiosensitivity of Glioma Cells in Vitro and in Vivo Clin. Cancer Res., August 1, 2003; 9(9): 3272 - 3281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ekmekcioglu, J. A. Ellerhorst, J. B. Mumm, M. Zheng, L. Broemeling, V. G. Prieto, A. L. Stewart, A. M. Mhashilkar, S. Chada, and E. A. Grimm Negative Association of Melanoma Differentiation-associated Gene (mda-7) and Inducible Nitric Oxide Synthase (iNOS) in Human Melanoma: MDA-7 Regulates iNOS Expression in Melanoma Cells Mol. Cancer Ther., January 1, 2003; 2(1): 9 - 17. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
