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The Atonal Proneural Transcription Factor Links Differentiation and Tumor Formation in Drosophila  [PDF]
Wouter Bossuyt,Natalie De Geest,Stein Aerts,Iris Leenaerts,Peter Marynen,Bassem A. Hassan
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000040
Abstract: The acquisition of terminal cell fate and onset of differentiation are instructed by cell type–specific master control genes. Loss of differentiation is frequently observed during cancer progression, but the underlying causes and mechanisms remain poorly understood. We tested the hypothesis that master regulators of differentiation may be key regulators of tumor formation. Using loss- and gain-of-function analyses in Drosophila, we describe a critical anti-oncogenic function for the atonal transcription factor in the fly retina, where atonal instructs tissue differentiation. In the tumor context, atonal acts by regulating cell proliferation and death via the JNK stress response pathway. Combined with evidence that atonal's mammalian homolog, ATOH1, is a tumor suppressor gene, our data support a critical, evolutionarily conserved, function for ato in oncogenesis.
The Atonal Proneural Transcription Factor Links Differentiation and Tumor Formation in Drosophila  [PDF]
Wouter Bossuyt,Natalie De Geest,Stein Aerts,Iris Leenaerts,Peter Marynen,Bassem A Hassan
PLOS Biology , 2009, DOI: 10.1371/journal.pbio.1000040
Abstract: The acquisition of terminal cell fate and onset of differentiation are instructed by cell type–specific master control genes. Loss of differentiation is frequently observed during cancer progression, but the underlying causes and mechanisms remain poorly understood. We tested the hypothesis that master regulators of differentiation may be key regulators of tumor formation. Using loss- and gain-of-function analyses in Drosophila, we describe a critical anti-oncogenic function for the atonal transcription factor in the fly retina, where atonal instructs tissue differentiation. In the tumor context, atonal acts by regulating cell proliferation and death via the JNK stress response pathway. Combined with evidence that atonal's mammalian homolog, ATOH1, is a tumor suppressor gene, our data support a critical, evolutionarily conserved, function for ato in oncogenesis.
Bunched, the Drosophila homolog of the mammalian tumor suppressor TSC-22, promotes cellular growth
Silvia Gluderer, Sean Oldham, Felix Rintelen, Andrea Sulzer, Corina Schütt, Xiaodong Wu, Laurel A Raftery, Ernst Hafen, Hugo Stocker
BMC Developmental Biology , 2008, DOI: 10.1186/1471-213x-8-10
Abstract: We have identified bun in an unbiased genetic screen for growth regulators in Drosophila. Rather unexpectedly, bun mutations result in a growth deficit. Under standard conditions, only the long protein isoform BunA – but not the short isoforms BunB and BunC – is essential and affects growth. Whereas reducing bunA function diminishes cell number and cell size, overexpression of the short isoforms BunB and BunC antagonizes bunA function.Our findings establish a growth-promoting function of Drosophila BunA. Since the published studies on mammalian systems have largely neglected the long TSC-22 protein version, we hypothesize that the long TSC-22 protein is a functional homolog of BunA in growth regulation, and that it is antagonized by the short TSC-22 protein.Tumorigenesis is frequently associated with a loss of a tumor suppressor, allowing tumor cells to become self-sufficient in growth signals, to become insensitive to growth-inhibitory signals, or to evade apoptosis (reviewed in [1]). Thus, the functional characterization of tumor suppressors is key to a better understanding of the signaling events leading to aberrant growth.Transforming Growth Factor-β1 stimulated clone-22 (TSC-22) is a putative negative growth regulator and tumor suppressor in mammals. TSC-22 has first been isolated as a TGF-β1 responsive gene from a mouse osteoblastic cell line [2]. It encodes a putative transcription factor that binds to DNA in vitro via its TSC-box [3]. TSC-22 expression has been found to be lowered in different mouse and human tumors, including liver [4], brain [5], prostate [6], and salivary gland tumors [7]. Consistently, downregulation of TSC-22 enhances growth in the salivary gland cell line TYS [7], whereas upregulation of TSC-22 is associated with apoptosis [8,9] and growth inhibition [10]. Increased TSC-22 expression also correlates with growth inhibition in primary human prostatic cancer cells [11,12]. Furthermore, in the mammary carcinoma cell line T47D, TSC-22 is a
Genomic characterization of the human mitochondrial tumor suppressor gene 1 (MTUS1): 5' cloning and preliminary analysis of the multiple gene promoters
Jinsheng Yu, Xiqiang Liu, Hui Ye, Xiaofeng Zhou
BMC Research Notes , 2009, DOI: 10.1186/1756-0500-2-109
Abstract: Here, we characterized the 5' untranslated regions of the different transcript variants. We also cloned and functionally tested the alternatively utilized gene promoters that contribute to the production of different MTUS1 transcript variants.Our results confirmed the early hypothesis that the transcript variants of MTUS1 gene are driven by multiple gene promoters.The MTUS1 gene is located in a region (8p22) that shows frequent loss of heterozygosity (LOH) in several tumor types, including oral cancer [1]. Alternative exon utilization leads to the production of 5 known transcript variants (designated as variant 1 to 5) [2]. It has been suggested that the long form of transcript variants (variant 1, 2, and 3) are driven by a common gene promoter, while variant 4 and 5 are driven by 2 additional promoters [2]. Variant 5 was the first transcript variant to be cloned independently in 2 laboratories, as a gene that is transiently upregulated during initiation of cell differentiation and quiescence [3]. It represents an early component of the growth-inhibiting signaling cascade that interacts with angiotensin II AT2 receptor [4]. Evidence supporting the tumor suppressor function of other MTUS1 variants comes from the study on Xenopus Icis gene, a homolog of MTUS1 variants 1 and 2, which regulates microtubule growth and spindle formation prior to anaphase [5]. Here, we refined the genomic structure of the MTUS1 gene and functionally cloned the alternatively utilized gene promoters that control the production of these MTUS1 transcript variants. This will enhance our understanding on the regulation of this candidate tumor suppressor gene.To characterize the 5' untranslated regions (5'-UTR) of the MTUS1 transcript variants, 5'-RACE assays were carried out using human brain reference mRNA (Ambion Inc) and a FirstChoice RLM-RACE kit from Ambion, with primers specific for various transcript variants (Additional file 1). The RACE products were PCR amplified, gel purified and then
Tumor suppressor gene methylation in follicular lymphoma: a comprehensive review
John Hayslip, Alberto Montero
Molecular Cancer , 2006, DOI: 10.1186/1476-4598-5-44
Abstract: Follicular lymphoma (FL), an indolent subgroup of non-hodgkin lymphomas, is a monoclonal lymphoid neoplasm arising from a malignant germinal center B lymphocyte. FL has an average annual incidence rate of 2.6 per 100,000 people and a median survival of 7.8 years [1,2].Recent molecular studies have established that activation of various oncogenes and silencing of tumor suppressor genes is required for FL development and progression. Here we discuss published literature regarding transcriptional silencing associated with DNA methylation in FL. In particular, we detail the genes known to be frequently methylated in FL, discuss their associated protein's function, and conclude with considerations for incorporating hypomethylating agents to reactivate methylated tumor suppressor genes as a novel therapeutic strategy for indolent and transformed FL.Tumor suppressor genes protect cells from undergoing malignant transformation. Tumor suppressor genes function by one of the following mechanisms: protect the genome from mutagenic events, impede dysregulated progression through the cell cycle, induce apoptosis in cells that escape normal cell cycle controls, and inhibit cellular migration and metastasis. Classically, tumor suppressor genes have been described to acquire loss of function mutations or deletions leading to their inability to impede malignant transformation. Alternatively, epigenetic events, such as methylation, represent a distinct mechanism of tumor suppressor gene inactivation. Aberrant gene promoter methylation is associated with gene silencing and is functionally equivalent to a deleted gene. Gene silencing by DNA methylation has been considered to be permanent in non-embryonic cells, only reversible pharmacologically during cell division. Interestingly, new findings in lymphocytes may challenge this paradigm of irreversibility but have yet to be widely replicated nor specifically studied in FL [3].The promoter region of a gene is located upstream, at the 5'
Transcriptional activation of the Lats1 tumor suppressor gene in tumors of CUX1 transgenic mice
Rania Siam, Ryoko Harada, Chantal Cadieux, Robert Battat, Charles Vadnais, Alain Nepveu
Molecular Cancer , 2009, DOI: 10.1186/1476-4598-8-60
Abstract: Genome-wide location arrays in cell lines of various cell types revealed that Lats1 was a transcriptional target of CUX1. Scanning ChIP analysis confirmed that CUX1 binds to the immediate promoter of Lats1. Expression of Lats1 was reduced in cux1-/- MEFs, whereas it was increased in cells stably or transiently expressing p110 or p75 CUX1. Reporter assays confirmed that the immediate promoter of Lats1 was sufficient to confer transcriptional activation by CUX1. Lats1 was found to be overexpressed in tumors from the mammary gland, uterus and spleen that arise in p110 or p75 CUX1 transgenic mice. In tissue culture, such elevated LATS1 expression did not hinder cell cycle progression in cells overexpressing p110 CUX1.While inactivation of Lats1/wts in mouse and Drosophila can increase cancer incidence, results from the present study demonstrate that Lats1 is a transcriptional target of CUX1 that can be overexpressed in tumors of various tissue-types. Interestingly, two other studies documented the overexpression of LATS1 in human cervical cancers and basal-like breast cancers. We conclude that, similarly to other genes involved in mitotic checkpoint, cancer can be associated with either loss-of-function or overexpression of Lats1.The large tumor suppressor (Lats)/Warts (wts) gene is conserved from insect to humans and codes for a serine/threonine kinase that was successively implicated as a tumor suppressor, a regulator of mitosis and a key component of the so-called Hippo pathway that controls the coordination between cell proliferation and apoptosis (reviewed in [1,2]). Mutations in the Drosophila lats1 homolog, warts (wts), were found originally to cause various developmental defects and dramatic overproliferation phenotypes including the development of tumors in various tissues [3,4]. Complementation assays in flies demonstrated that the human LATS1 gene was able to suppress tumour growth and rescue all developmental defects of wts mutants including embryonic lethal
TUSC1, a Putative Tumor Suppressor Gene, Reduces Tumor Cell Growth In Vitro and Tumor Growth In Vivo  [PDF]
Zhihong Shan, Abbas Shakoori, Sohrab Bodaghi, Paul Goldsmith, Jen Jin, Jonathan S. Wiest
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066114
Abstract: We previously reported the identification of TUSC1 (Tumor Suppressor Candidate 1), as a novel intronless gene isolated from a region of homozygous deletion at D9S126 on chromosome 9p in human lung cancer. In this study, we examine the differential expression of TUSC1 in human lung cancer cell lines by western blot and in a primary human lung cancer tissue microarray by immunohistochemical analysis. We also tested the functional activities and mechanisms of TUSC1 as a tumor suppressor gene through growth suppression in vitro and in vivo. The results showed no expression of TUSC1 in TUSC1 homozygously deleted cells and diminished expression in some tumor cell lines without TUSC1 deletion. Interestingly, the results from a primary human lung cancer tissue microarray suggested that higher expression of TUSC1 was correlated with increased survival times for lung cancer patients. Our data demonstrated that growth curves of tumor cell lines transfected with TUSC1 grew slower in vitro than those transfected with the empty vector. More importantly, xenograph tumors in nude mice grew significantly slower in vivo in cells stably transfected with TUSC1 than those transfected with empty vector. In addition, results from confocal microscopy and immunohistochemical analyses show distribution of TUSC1 in the cytoplasm and nucleus in tumor cell lines and in normal and tumor cells in the lung cancer tissue microarray. Taken together, our results support TUSC1 has tumor suppressor activity as a candidate tumor suppressor gene located on chromosome 9p.
P15—A new tumor suppressor gene
Yingkai Tong,Huitu Liu
Chinese Science Bulletin , 1999, DOI: 10.1007/BF02885957
Abstract: In addition to the tumor suppressor genes such asRb andp53, it has been found that some molecules of the same class named CKI (cyclin-dependent kinase inhibitor) also play an important role in the inhibition of tumorigenesis and the tumor progression. In the KIP and INK4 families of CKls,p15 shares extensive homology withp16. Findings in many tumors and their cell lines show that the inactivation ofp15 (deletion, mutation, rearrangement, etc.) is very frequent, and inactivep15 is involved in the progress of some tumors. These studies provide evidence that thep15 is a new tumor suppressor gene. Furthermore, the research on the molecular mechanism ofp15 in regulation of cell proliferation shows thatp15 can inhibit the growth of some kinds of tumor cells, andp15 is the mediator of TGF-β-induced cell arrest. Investigations onp15 in cell differentiation suggest that increasedp15 is related to the change of malignant phenotype. These results supply clues for further interpretation about the molecular mechnism of cell cycle control and cell tumorigenesis. And they may provide theoretical and experimental basis for application ofp15 to clinical therapy of tumors.
P53 and Rb tumor suppressor gene alterations in gastric cancer
Mattar, Rejane;Nonogaki, Suely;Silva, Cleonice;Alves, Venancio;Gama-Rodrigues, Joaquim J.;
Revista do Hospital das Clínicas , 2004, DOI: 10.1590/S0041-87812004000400004
Abstract: inactivation of tumor suppressor genes has been frequently observed in gastric carcinogenesis. our purpose was to study the involvement of p53, apc, dcc, and rb genes in gastric carcinoma. method: loss of heterozygosity of the p53, apc, dcc and rb genes was studied in 22 gastric cancer tissues using polymerase chain reaction; single-strand conformation polymorphism of the p53 gene exons 5-6 and exons 7-8 was studied using 35s-datp, and p53 expression was detected using a histological immunoperoxidase method with an anti-p53 clone. results and discussion: no loss of heterozygosity was observed in any of these tumor suppressor genes; homozygous deletion was detected in the rb gene in 23% (3/13) of the cases of intestinal-type gastric carcinoma. eighteen (81.8%) cases showed band mobility shifts in exons 5-6 and/or 7-8 of the p53 gene. the presence of the p53 protein was positive in gastric cancer cells in 14 cases (63.6%). normal gastric mucosa showed negative staining for p53; thus, the immunoreactivity was likely to represent mutant forms. the correlation of band mobility shift and the immunoreactivity to anti-p53 was not significant (p = .90). there was no correlation of gene alterations with the disease severity. conclusions: the inactivation of rb and p53 genes is involved in gastric carcinogenesis in our environment. loss of the rb gene observed only in the intestinal-type gastric cancer should be further evaluated in association with helicobacter pylori infection. the p53 gene was affected in both intestinal and diffuse histological types of gastric cancer.
Tumor Suppressor Gene-Based Nanotherapy: From Test Tube to the Clinic  [PDF]
Manish Shanker,Jiankang Jin,Cynthia D. Branch,Shinya Miyamoto,Elizabeth A. Grimm,Jack A. Roth,Rajagopal Ramesh
Journal of Drug Delivery , 2011, DOI: 10.1155/2011/465845
Abstract: Cancer is a major health problem in the world. Advances made in cancer therapy have improved the survival of patients in certain types of cancer. However, the overall five-year survival has not significantly improved in the majority of cancer types. Major challenges encountered in having effective cancer therapy are development of drug resistance by the tumor cells, nonspecific cytotoxicity, and inability to affect metastatic tumors by the chemodrugs. Overcoming these challenges requires development and testing of novel therapies. One attractive cancer therapeutic approach is cancer gene therapy. Several laboratories including the authors' laboratory have been investigating nonviral formulations for delivering therapeutic genes as a mode for effective cancer therapy. In this paper the authors will summarize their experience in the development and testing of a cationic lipid-based nanocarrier formulation and the results from their preclinical studies leading to a Phase I clinical trial for nonsmall cell lung cancer. Their nanocarrier formulation containing therapeutic genes such as tumor suppressor genes when administered intravenously effectively controls metastatic tumor growth. Additional Phase I clinical trials based on the results of their nanocarrier formulation have been initiated or proposed for treatment of cancer of the breast, ovary, pancreas, and metastatic melanoma, and will be discussed.
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