bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1973: Tumor suppressor p15Ink4b determines cell fate of hematopoietic progenitors: Implications for development of human blood disorders.
Authors: Humeniuk Rita , Rosu-Myles Michael , Wolff Linda 
Published: August 2014

Abstract
Red blood cells (RBCs) are a vital component of mammalian blood. Since they are short lived, they must be continuously replenished by erythropoiesis, a stepwise commitment of blood stem and progenitor cells to mature erythrocytes. The anemia due to the loss of RBC is a life threatening condition, often accompanying blood diseases such as leukemias and myelodysplastic syndromes (MDS). A striking 60-80% of these diseases have deleted or silenced expression of p15INK4B. An increased understanding of the factors that drive erythroid lineage commitment in progenitor cells is critical for developing new treatments for blood disorders. Previous examination of p15Ink4b knock-out mouse models, revealed skewing of hematopoietic progenitor differentiation towards myeloid lineage (granulocytes, macrophages). Here, we demonstrate a novel function for p15Ink4b in driving commitment to the erythroid lineage. Mice lacking p15Ink4b have lower numbers of primitive RBC progenitors and died shortly after induction of hemolytic anemia by phenylhydrazine injection. Expression of p15Ink4b in blood progenitors induced dynamic changes at the molecular level that rendered multi-lineage cells more permissive to erythroid commitment and less permissive to myeloid commitment. Noticeably, we found that p15Ink4b regulates a switch that controls the balance between myeloid and erythroid differentiation through activation of MEK/ERK signaling. In a time-coordinated manner expression of p15Ink4b induced rapid phosphorylation of MEK/ERK that led to rapid degradation of GATA-2 and activation of the GATA-1 transcription factors. Subsequently, the active GATA-1 executed lineage commitment through activation of the Erythropoietin receptor (EpoR), the “master regulator” of erythroid differentiation. The p15Ink4b mediated increase in GATA-1 expression, also resulted in decreased expression of the myeloid specific transcription factor PU.1, suppressing myeloid differentiation. In summary, we have defined a framework that determines how multipotent progenitors coordinate the balance between myeloid and erythroid differentiation. Central to this activity is p15Ink4b, which promotes erythroid fate while suppressing myeloid cell formation, a function that is particularly important in rapid RBC replenishment following stress. Our finding has implications not only for MDS and myeloid leukemia, where loss of tumor suppressor p15INK4B is a common event, but also for other forms of human refractory anemia.
Citation Format: Rita Humeniuk, Michael Rosu-Myles, Linda Wolff. Tumor suppressor p15Ink4b determines cell fate of hematopoietic progenitors: Implications for development of human blood disorders. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1973. doi:10.1158/1538-7445.AM2013-1973
Abstract 1977: The protein phosphatase 2 subunit PR48 is a novel melanoma tumor suppressor gene.
Authors: van Kempen Léon CL , Jarry Jonathan , Elchebly Mounib , Redpath Margaret , Edqvist Per-Henrík , Pontén Fredrik , Scolyer Richard , Schadendorf Dirk , Greenwood Celia M.T. , van den Oord Joost , Spatz Alan 
Published: August 2014

Abstract
Cutaneous melanoma cell proliferation is a strong prognostic factor for distant metastasis free survival (DMFS). In the current study we tested if aberrant expression of a regulator both DNA replication and cell cycle progression, i.e. the protein phosphatase 2A subunit PR48, could be a driver of melanoma proliferation and progression. Quantitative analysis of PR48 mRNA expression revealed a strong correlation between low levels of expression and poor DMFS in a multivariate analysis (n=49, p=0.0007). In line with this, no or low PR48 protein expression was associated with poor overall survival in three independent samples sets of melanoma (n=339, P&lt;0.001), and reduced PR48 expression correlated with increased proliferation (P=0.0023). Functional analysis using over expression and knock down strategies in melanoma cell lines demonstrated that PR48 alters cdc6-cdt1 complex formation, regulates pRb phosphorylation status, and entry into the S-phase of the cycle progression. Ectopic PR48 expression decreased tumorigenicity of melanoma cells, and shRNA-mediated reduced PR48 expression increased tumor take and growth in nude mice. Our data demonstrate that PPP2R3B is a novel tumor suppressor gene in melanoma, whose loss of expression contributes increased proliferation and poor survival.
Citation Format: Léon CL van Kempen, Jonathan Jarry, Mounib Elchebly, Margaret Redpath, Per-Henrík Edqvist, Fredrik Pontén, Richard Scolyer, Dirk Schadendorf, Celia M.T. Greenwood, Joost van den Oord, Alan Spatz. The protein phosphatase 2 subunit PR48 is a novel melanoma tumor suppressor gene. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1977. doi:10.1158/1538-7445.AM2013-1977
Abstract 1978: Demonstrating a role for nuclear Adenomatous polyposis coli in intestinal cell differentiation.
Authors: Miller Matthew A. , Zeineldin Maged , Neufeld Kristi L. 
Published: August 2014

Abstract
Colon cancer is the second leading cause of cancer-related mortality in the United States, resulting in over 50,000 deaths annually. Approximately 80% of colon cancers begin with a mutation in the gene coding for the tumor suppressor protein Adenomatous Polyposis Coli, APC. APC protein can shuttle between the cytoplasm and the nucleus of cells, facilitated by two nuclear localization signals (NLS) and multiple nuclear export signals. To better understand functions of nuclear APC, our lab generated a “knock-in” mouse model with mutations introduced that inactivate both Apc NLS. These ApcmNLS/mNLS mice show a dramatic decrease in nuclear Apc. We previously showed increased proliferation and Wnt target gene expression in intestinal epithelial cells from ApcmNLS/mNLS mice, suggesting a role for nuclear APC in inhibition of proliferation and Wnt signaling. We also showed increased tumor number and size in ApcMin mice if they also harbor the ApcmNLS allele. Here we examine the role of nuclear Apc in intestinal epithelial differentiation and stem cell homeostasis. Paraffin-embedded tissue from the intestines of Apc+/+ and ApcmNLS/mNLS mice was sectioned and stained for markers of enterocytes (alkaline phosphatase) and goblet cells (alcian blue). Quantification of the positive cells indicated that ApcmNLS/mNLS mice had fewer differentiated enterocytes and goblet cells than their wild-type littermates. Intestines from ApcmNLS/mNLS mice were also stained for markers of quiescent and active stem cells, DCAMKL-1 and Lgr5 respectively. Quantification of the various stem cell populations will be described. Together, our data supports a role for nuclear Apc in promoting enterocyte and goblet cell differentiation, in suppression of tumors, and in inhibiting intestinal cell proliferation and Wnt signaling. Information gathered from analysis of ApcmNLS/mNLS mice will contribute to our understanding of the functions of nuclear APC in tumor suppression and ultimately the mechanism of intestinal tumorigenesis.
Citation Format: Matthew A. Miller, Maged Zeineldin, Kristi L. Neufeld. Demonstrating a role for nuclear Adenomatous polyposis coli in intestinal cell differentiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1978. doi:10.1158/1538-7445.AM2013-1978
Abstract 1981: Ephrin B2 as a tumor suppressor in breast cancer.
Authors: Perez-Tenorio Gizeh , Stål Olle , Pasquale Elena B. 
Published: August 2014

Abstract
The EphB4 is a tyrosine kinase receptor with both tumor suppressor and promoting activities. The role of EphB4 in breast cancer is not fully elucidated. EphB-receptors transmit forward and reverse signals, which together are known as bidirectional signals. EphB4 reverse signaling, mediated by the ephrin-B2 ligand expressed in endothelial cells, causes some of the oncogenic properties of the receptor. In contrast, EphB4 forward signaling suppresses tumor growth. In breast cancers with high EphB4-receptor expression the forward signaling activity is low due to low expression of ephrin-B2. In fact, the EFNB2 gene, encoding ephrin-B2, is located on chromosome 13, which is lost in more than 30% of breast cancers. Our hypothesis was that ephrin-B2 re-expression in tumors could restore EphB4-forward signal inhibiting tumor growth. To examine the effects of EphB4-ephrin-B2 co-expression in vitro, we used lentiviral vectors to stably infect MCF7 cells with ephrin-B2. We found in vitro that ephrin-B2 expression caused cell detachment, inhibited cell proliferation; focus formation and cell motility, all characteristics of tumor suppression. Likewise, in patient materials we observed that high ephrin-B2 mRNA levels correlated with better distant recurrence-free survival. Interestingly, low ephrin-B2 expression identifies the group of worse prognosis among patients with high EphB4 and HER-2 expression in terms of distant recurrence and breast cancer survival. Taken together these results support our hypothesis and suggest that ephrin-B2 may be a tumor suppressor and a novel prognostic marker in breast cancer.
Citation Format: Gizeh Perez-Tenorio, Olle Stål, Elena B. Pasquale. Ephrin B2 as a tumor suppressor in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1981. doi:10.1158/1538-7445.AM2013-1981
Abstract 1983: Functional analysis of cancer-associated mutations in human LATS1 and LATS2 tumor suppressors.
Authors: Yu Tian , Bachman John F. , Lai Zhi-Chun 
Published: August 2014

Abstract
Large Tumor Suppressor LATS1 and LATS2 (LATS1/2) are the key kinases of the hippo pathway, which regulates organ size and tumorigenesis in Drosophila and mammals in an evolutionary conserved pattern. Lats1 deficient mice develop soft tissue sarcomas, while disruption of Lats2 in mice and lats(wts) in Drosophila cause embryonic lethality. The Cancer Genome Project has identified 31 Lats1 and 21 Lats2 somatic mutations in the primary tumor tissues from a variety of human cancers, such as lung and ovarian cancer. However, the consequences of these mutations are still to be elucidated. In our study, evolutionary conservation analysis and structure remodeling predict 9 potentially damaging missense mutations, seven of which are located in the kinase domain. Immunoblotting demonstrates that one of the LATS2 mutants does not encode the protein product, whereas the other LATS1/2 mutants impair their phosphorylation, and attenuate their kinase activities on phosphorylating oncogene YAP. Furthermore, luciferase-based reporter assay shows that transcriptional coactivator activity of YAP is inhibited by wild type LATS1/2, but not by the mutants. In addition, in vivo transgenic expressions of LATS1/2 mutants result in less growth suppression in the Drosophila wing, when compared with the wild type. LATS1/2 mutants also fail to fully rescue the lethality causing by endogenous lats(wts) knockdown. Together, these results suggest that human LATS1 and LATS2 mutations deregulate oncogene YAP and highlight the crucial role of hippo pathway control in tumor suppression.
Citation Format: Tian Yu, John F. Bachman, Zhi-Chun Lai. Functional analysis of cancer-associated mutations in human LATS1 and LATS2 tumor suppressors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1983. doi:10.1158/1538-7445.AM2013-1983
Abstract 1985: ZNF783, a novel zinc finger protein has tumor suppressor function in prostate cancer.
Authors: Tbaishat Rana , Wang Songping , Kwabi-Addo Bernard 
Published: August 2014

Abstract
In the last decade hypermethylation of promoter regions has been accepted to be a prominent feature of human tumorigenesis by silencing tumor suppressor genes and other genes involved in cellular pathways. To study more in depth the involvement of aberrant methylation in prostate cancer tumorigenesis, we used a genome wide methylation array from
Illumina (Infunium) to identify novel hypermethylated genes that might contribute to prostate cancer progression. ZNF783 is one such candidate gene. ZNF783 is
Zinc-finger transcription factor that maps to human chromosome 7q33, a region implicated in prostate cancer tumorigenesis. We have observed significant hypermethylation of ZNF783 promoter CpG island in prostate cancer cell lines and prostate tumors when compared to match normal prostate tissue samples from radical prostatectomy patients. The treatment of prostate cancer cell lines with pharmacological demethylating agents restored ZNF783 gene expression indicating
a role for epigenetic DNA methylation in regulating ZNF783 expression in prostate cancer. The ZNF family of proteins has been identified to play essential roles in gene expression/regulation including inhibition of cell cycle proliferation, differentiation and apoptosis. The current study demonstrates a potential tumor suppressor role for ZNF783 in prostate cancer cells.
Citation Format: Rana Tbaishat, Songping Wang, Bernard Kwabi-Addo. ZNF783, a novel zinc finger protein has tumor suppressor function in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1985. doi:10.1158/1538-7445.AM2013-1985
Abstract 1986: Tumor suppressor PDCD4 inhibits NFκB dependent transcription in human glioblastoma cells by direct interaction with p65.
Authors: Hwang Soon-Kyung , Young Matthew R. , Colburn Nancy H. 
Published: August 2014

Abstract
PDCD4 was first described as a protein induced by apoptotic stimuli that acts as a tumor suppressor. PDCD4 plays an important role in regulating translation and transcription. Our previous research showed that overexpression of PDCD4 leads to decreased anchorage independent growth in glioblastoma-derived cell lines as well as decreased tumor growth in a glioblastoma xenograft model. Moreover, PDCD4 positively influences tumor necrosis factor-induced activation of the transcription factor NF-κB in inflammatory cells. However, the effect of PDCD4 on NF-κB transcriptional activity in cancer cells is still unknown. NF-κB acts as an oncogenic driver in many cancer sites. We studied the effect of PDCD4 on NF-κB-dependent transcriptional activity in malignant human glioblastoma cell lines by stably overexpressing PDCD4 in GBM U251 and LN229 cells. Stable Pdcd4 expression inhibits NF-κB transcriptional activation measured by a luciferase reporter in U251 and LN229 cells. The molecular mechanism by which PDCD4 inhibits NF-κB transcriptional activation does not involve inhibited expression of NF-κB p65 or p50 proteins. PDCD4 overexpression does not inhibit pathways upstream of NF-κB including the activation of IKKalpha and IKKbeta kinases. In addition, PDCD4 does not inhibit phosphorylation or degradation of IκBα, events needed for nuclear transport of p65 and p50. Overexpression of PDCD4 does, however, inhibit translocation of p65 but not p50 to the nucleus. Pdcd4 protein interacts directly with p65 protein as shown by co-immunoprecipitation and confocal imaging. These results suggest that PDCD4 can significantly inhibit NF-κB activity in glioblastoma cells by a mechanism that involves direct protein-protein interaction rather than the expected mRNA-selective translational inhibition. These findings may provide novel opportunities for NF-κB targeted interventions to prevent or treat cancer.
Citation Format: Soon-Kyung Hwang, Matthew R. Young, Nancy H. Colburn. Tumor suppressor PDCD4 inhibits NFκB dependent transcription in human glioblastoma cells by direct interaction with p65. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1986. doi:10.1158/1538-7445.AM2013-1986
Abstract 1988: Divergent control of Cav-1 expression in non-cancerous Li-Fraumeni Syndrome and human cancer cell lines.
Authors: Sherif Zaki A. , Sultan Ahmed S. 
Published: August 2014

Abstract
Li-Fraumeni Syndrome (LFS) is primarily characterized by development of tumors exhibiting germ-line mutations in the p53 gene. Cell lines developed from patients of a LFS family have decreased p53 activity as evidenced by the absence of apoptosis upon etoposide treatment. To test our hypothesis that changes in gene expression beyond p53 per se are contributing to the development of tumors, we compared gene expression in non-cancerous skin fibroblasts of LFS-affected (p53 heterozygous) versus non-affected (p53 wild-type homozygous) family members. Expression analysis showed that several genes were differentially regulated in the p53 homozygous and heterozygous cell lines. We were particularly intrigued by the decreased expression (∼88%) of a putative tumor suppressor protein, caveolin-1 (Cav-1), in the p53-mutant cells. Decreased expression of Cav-1 was also seen in both p53-knockout and p21-knockout HTC116 cells suggesting that p53 controls Cav-1 expression through p21 and leading to the speculation that p53, Cav-1 and p21may be part of a positive auto-regulatory feedback loop. The direct relationship between p53 and Cav-1 was also tested with HeLa cells (containing inactive p53), which expressed a significantly lower Cav-1 protein. A panel of nonfunctional and p53-deficient colon and epithelial breast cancer cell lines showed undetectable expression of Cav-1 supporting the role of p53 in the control of Cav-1. However, in two aggressively metastasizing breast cancer cell lines, Cav-1 was strongly expressed suggesting a possible role in tumor metastasis. Thus, there is a divergent control of Cav-1 expression as evidenced in non-cancerous Li-Fraumeni Syndrome and some aggressive human cancer cell lines.
Citation Format: Zaki A. Sherif, Ahmed S. Sultan. Divergent control of Cav-1 expression in non-cancerous Li-Fraumeni Syndrome and human cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1988. doi:10.1158/1538-7445.AM2013-1988
Abstract 1989: ASPP2 enhances DRAM induced autophagy to promote apoptosis in HepG2 cells.
Authors: Liu Kai , Wen Tao , Yin Ming Ji , Qiao Xin Lu , Shi Ying , Li Li , Liu Jie Dao , Zhang Chao , Li Ning , Lopez Charles , Chen Xi De 
Published: August 2014

Abstract
Background and Aims: ASPP2 (Apoptosis Stimulating Protein 2 of p53) binds to p53 and enhances p53 pro-apoptotic function. Autophagy may play a role in this process although the mechanisms remain to be clarified. Our aims were to explore the mechanisms by which the ASPP2-p53 pathway could promote apoptosis and autophagy in hepatocellular carcinoma cells in order to identify novel therapeutic targets in this disease.
Methods: HepG2 cells were transfected with GFP-LC3 plasmid and then damaged with methyl methanesulfonate (MMS). Apoptosis was detected by cleavage of CK18 and PARP by immunocytochemical staining and Western blot. Real-time PCR and immunoblot were used to analyze changes in DRAM and LC3I/II expression. DRAM siRNA was used to inhibit DRAM function.
Results: After MMS exposure for 24 hours, we identified more M30 positive cells and p85 formation in HepG2 cells compared to control cells. When HepG2 cells were transfected with a GFP-LC3 expression plasmid and then treated by MMS, we found that MMS treatment induced LC3 staining punctate structures, a marker for autophagy. Moreover, enforced expression of ASPP2 using adenovirus infection led to more autophagy and apoptosis in HepG2 after MMS treatment, under conditions where ASPP2 expressing adenovirus infection alone could not induce apoptosis and autophagy. Using real time PCR, we identified that MMS treatment could induce DRAM expression and that ASPP2 overexpression prior to MMS could further enhance DRAM expression compared to MMS alone. Immunoblot assay demonstrated that ASPP2 expression increased MMS-induced DRAM expression, LC3 II and p85 formation. Importantly, a DRAM specific siRNA blocked autophagy and apoptosis in HepG2 cells under these conditions when compared to a control siRNA.
Conclusions: Our results suggest that ASPP2 can enhance MMS induced apoptosis via p53-dependent DRAM-mediated autophagy. Since DRAM is an important component of p53-mediated autophagy, our results demonstrate a new role for ASPP2 in this pathway. These findings open new avenues for investigation into the mechanisms of autophagy-based therapy in hepatocellular cancer (Supported by National Natural Science Foundation of China (30870853,30770742 and 30910103915), Beijing Municipal Natural Science Foundation (7092045 and 7101005) and Basic-Clinical Collaborative Research Fund, CCMU (12JL-L05)).
Citation Format: Kai Liu, Tao Wen, Ming Ji Yin, Xin Lu Qiao, Ying Shi, Li Li, Jie Dao Liu, Chao Zhang, Ning Li, Charles Lopez, Xi De Chen. ASPP2 enhances DRAM induced autophagy to promote apoptosis in HepG2 cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1989. doi:10.1158/1538-7445.AM2013-1989