Biomedical subjects

E J Stanbridge

Publications and source records attributed to E J Stanbridge.

At least 37 records · Page 2Linked to original sources

PubMed2000

p53-mediated negative regulation of stathmin/Op18 expression is associated with G(2)/M cell-cycle arrest.

Utilizing the technique of differential display of mRNA, we have identified p53-responsive genes that are transcriptionally up- or down-regulated as cells enter growth arrest. One gene that was down-regulated, pong16, was found to be identical to stathmin/Op18, a protein involved in the regulation of microtubule dynamics. Evidence that p53 is directly or indirectly involved in negative regulation of stathmin/Op18 expression includes the following: (i) p53-mediated growth inhibition is associated with repression of stathmin/Op18 expression following serum stimulation, (ii) reporter gene assays revealed p53-mediated repression of stathmin/Op18 promoter activity and (iii) constitutive over-expression of stathmin/Op18 bypasses a p53-mediated G(2)/M arrest in the cell cycle. These results suggest that p53-mediated negative regulation of stathmin/Op18 plays an important role in cell-cycle control.

Down-Regulation↗

PubMed2000

Direct evidence for the contribution of activated N-ras and K-ras oncogenes to increased intrinsic radiation resistance in human tumor cell lines.

Transformation with ras oncogenes results in increased radiation sur vival in many but not all cells. In addition, prenyltransferase inhibitors which inhibit ras proteins by blocking posttranslational modification radiosensitize cells with oncogenic ras. These findings suggest that oncogenic ras contributes to intrinsic radiation resistance. However, because introduction of ras oncogenes does not increase radiation survival in all cells and because prenyltransferase inhibitors target molecules other than ras, these studies left the conclusion that ras increases the intrinsic radi ation resistance of tumor cells in doubt. Here we show that genetic inactivation of K- or N-ras oncogenes in human tumor cells (DLD-1 and HT1080, respectively) leads to increased radiosensitivity. Reintroduction of the activated N-ras gene into the HT1080 line, having lost its mutant allele, resulted in increased radiation resistance. This study lends further support to the hypothesis that expression of activated ras can contribute to intrinsic radiation resistance in human tumor cells and extends this finding to the K- and N- members of the ras family. These findings support the development of strategies that target ras for inactivation in the treatment of cancer.

Adenocarcinoma↗

PubMed2000

Expression of MN/CA9 protein in Papanicolaou smears containing atypical glandular cells of undetermined significance is a diagnostic biomarker of cervical dysplasia and neoplasia.

BACKGROUND: Despite the enormous impact that Papanicolaou (Pap) smear screening has had on the incidence of cervical carcinoma in developed countries, there is still an unacceptably high frequency of occurrence of this cancer. In part, this is due to human error associated with cytologic diagnoses of Pap smears. Also, the use of new sampling devices, such as the cytobrush, has increased the complexity of diagnosing benign and neoplastic cervical cytology. This is particularly apparent in the diagnosis of atypical glandular cells of undetermined significance (AGUS). Approximately 40% of AGUS diagnoses have a corresponding significant lesion at biopsy follow-up, and 60% do not. There is clearly a need for an adjunct to cytologic diagnosis that can readily identify AGUS smears that are diagnostic of significant lesions. The authors have identified the MN/CA9 antigen as a strong candidate for an adjunct biomarker. METHODS: A total of 245 Pap smears of all AGUS diagnostic categories with histologic confirmation were studied. The median age of the patients was 39 years. The Bethesda system classification (AGUS-favor reactive, AGUS-not otherwise specified, and AGUS-favor neoplastic) was used. All of the Pap smears were decolorized and immunostained with monoclonal antibody to MN/CA9 antigen by the immunoperoxidase technique. The results of MN/CA9 immunoreactivity were correlated with the histologic data in a semiblinded fashion. RESULTS: The follow-up biopsies showed that a high percentage (70%) of patients had low and high grade cervical intraepithelial neoplasia lesions, respectively (CIN I and CIN II or III). Clinically significant lesions-adenocarcinoma in situ/carcinoma (AIS/CA) and CIN II or III-were found in 50% of the cases. Among these, 11% were AIS/CA. In the three subcategories of AGUS diagnosis, the AGUS-not otherwise specified showed the broadest range of lesions in the follow-up biopsies. Three patterns of MN/CA9 immunoreactivity were observed in the Pap smears: 1) atypical cells, 2) normal endocervical cells only, and 3) all cells negative. All Pap smears that were MN/CA9 positive were histologically confirmed to be clinically significant lesions or CIN I; in addition, there were a very small number (n = 12) of cases of atypia. None of the benign lesions showed MN/CA9 expression in the corresponding Pap smears. Furthermore, the pattern of atypical cell immunostaining identified all cases with significant lesions (AIS/CA and CIN II or III) in the cervices. Conversely, the majority of CIN I cases (82%) and all cases of atypia showed positive immunostaining restricted to normal endocervical cells only. CONCLUSIONS: There is a clear association between MN/CA9 immunostaining of atypical cells and the presence of significant lesions in the cervix. Similarly, there is a clear association between lack of expression of MN/CA9 and the absence of cervical lesions. However, the screen does not allow discrimination between CIN I and atypia. The authors also found that, based on the combined patterns of morphology and immunostaining, they are able to discriminate between AIS and CIN II or III in AGUS Pap smear diagnoses. Thus, expression of the MN/CA9 antigen is indeed a discriminator of significant lesions in AGUS Pap smear diagnoses.

Adult↗

PubMed2000

A functional investigation of tumor suppressor gene activities in a nasopharyngeal carcinoma cell line HONE1 using a monochromosome transfer approach.

Monochromosome transfers of selected chromosomes into a nasopharyngeal carcinoma (NPC) cell line were performed to determine if tumor suppressing activity for NPC mapped to chromosomes 9, 11, and 17. Current information from cytogenetic and molecular allelotyping studies indicate that these chromosomes may harbor potential tumor suppressor genes vital to NPC. The present results show the importance of CDKN2A on chromosome 9 in NPC development. There was no functional suppression of tumor development in nude mice with microcell hybrids harboring the newly transferred chromosome 9 containing an interstitial deletion at 9p21, whereas transfection of CDKN2A into the NPC HONE1 cells resulted in obvious growth suppression. Whereas intact chromosome 17 transfers into HONE1 cells showed no functional suppression of tumor formation, chromosome 11 was able to do so. Molecular analysis of chromosome 11 tumor segregants indicated that at least two tumor suppressive regions mapping to 11q13 and 11q22-23 may be critical for the development of NPC.

Animals↗

PubMed2000

Interstitial deletion of 11q13 sequences in HeLa cells.

Previous cytogenetic and molecular genetic studies have shown that the HeLa (cervical carcinoma) cell line D98/AH-2 contains two apparently normal copies of chromosome 11 and additional 11q13-25 material translocated onto a chromosome 3 marker. To determine the 11q13 breakpoint, we performed fluorescence in situ hybridization (FISH) using 18 different 11q13 specific BAC (bacterial artificial chromosome) and cosmid probes spanning a 5.6 Mb interval. Markers localized to the multiple endocrine neoplasia type 1 (MEN1) gene (menin) were also included in the analysis. The FISH study identified an interstitial deletion between markers D11S449 and GSTP1, an interval of 2.3 Mb, in the marker chromosome. This deletion did not include the MEN1 gene. Because point mutations and methylations can inactivate the MEN1 gene, single stranded conformational polymorphism (SSCP) and Northern and Western blot analyses were performed with MEN1 specific probes and antibody. SSCP did not reveal mutations of the MEN1 gene in HeLa or in seven other cervical cancer cell lines. Northern and Western blot studies revealed normal levels of expression of this gene in the cervical cancer cell lines as well as in HeLa cell derived tumorigenic hybrids. Because deletions of tumor suppressor genes often occur in cancer progression, we hypothesize that the inactivation of a tumor suppressor gene other than MEN1, localized to the 2.3 Mb interval on 11q13, might play a role in the abnormal growth behavior of HeLa cells in vitro or in vivo.

Cell Transformation, Neoplastic↗

PubMed2000

Dissection of Ras-dependent signaling pathways controlling aggressive tumor growth of human fibrosarcoma cells: evidence for a potential novel pathway.

Activation of multiple signaling pathways is required to trigger the full spectrum of in vitro and in vivo phenotypic traits associated with neoplastic transformation by oncogenic Ras. To determine which of these pathways are important for N-ras tumorigenesis in human cancer cells and also to investigate the possibility of cross talk among the pathways, we have utilized a human fibrosarcoma cell line (HT1080), which contains an endogenous mutated allele of the N-ras gene, and its derivative (MCH603c8), which lacks the mutant N-ras allele. We have stably transfected MCH603c8 and HT1080 cells with activating or dominant-negative mutant cDNAs, respectively, of various components of the Raf, Rac, and RhoA pathways. In previous studies with these cell lines we showed that loss of mutant Ras function results in dramatic changes in the in vitro phenotypic traits and conversion to a weakly tumorigenic phenotype in vivo. We report here that only overexpression of activated MEK contributed significantly to the conversion of MCH603c8 cells to an aggressive tumorigenic phenotype. Furthermore, we have demonstrated that blocking the constitutive activation of the Raf-MEK, Rac, or RhoA pathway alone is not sufficient to block the aggressive tumorigenic phenotype of HT1080, despite affecting a number of in vitro-transformed phenotypic traits. We have also demonstrated the possibility of bidirectional cross talk between the Raf-MEK-ERK pathway and the Rac-JNK or RhoA pathway. Finally, overexpression of activated MEK in MCH603c8 cells appears to result in the activation of an as-yet-unidentified target(s) that is critical for the aggressive tumorigenic phenotype.

Animals↗

PubMed2000

p53 mutants have selective dominant-negative effects on apoptosis but not growth arrest in human cancer cell lines.

A bidirectional expression vector that allowed equal transcription of cloned wild-type and mutant p53 cDNAs from the same vector was developed. The vector was transfected into CaLu 6 lung carcinoma cells or Saos-2 osteosarcoma cells. All p53 mutants examined were recessive to wild-type p53 transactivation of p21(WAF1/CIP1) but dominant-negative for transactivation of Bax. An examination of effects on growth arrest and apoptotic pathways indicated that all mutants were recessive to wild type for growth arrest but only three of seven mutants were dominant negative for induction of apoptosis.

Apoptosis↗

PubMed2000

Prolonged cell cycle arrest in irradiated human diploid skin fibroblasts: the role of nutrient deprivation.

Ionizing radiation has been reported to cause an irreversible cell cycle arrest in normal human diploid fibroblasts. However, colony survival assays show that even at high doses of gamma radiation, human diploid fibroblasts do not irreversibly arrest, and that a dose-dependent fraction is capable of continued cycling. In this study, we resolve the apparent discrepancy between colony survival assays and the observed radiation-induced prolonged arrest. Using flow cytometry analysis, we have confirmed that human diploid fibroblasts do exhibit a prolonged cell cycle arrest in both G(1) and G(2)/M phases of the cell cycle. However, a single replacement of fresh growth medium stimulated a fraction of the arrested population of cells to transiently re-enter the cell cycle. Daily medium changes stimulated these irradiated human diploid fibroblasts to continue cycling until they were contact-inhibited. Thus the fraction of human diploid fibroblasts which survive radiation exposure and are capable of cycling appears to permanently arrest as a result of nutrient insufficiency. Western blot analysis demonstrated a radiation-induced elevation in TP53 (formerly known as p53) protein levels within 2 h postirradiation, followed by a decrease to levels comparable to those in unirradiated controls. The TP53 and CDKN1A (formerly known as p21) protein levels were indistinguishable after 24 h and remained elevated for a 6-day period of observation in both control and irradiated cultures. Our studies indicate that human diploid fibroblasts are capable of re-entering the cell cycle after exposure to ionizing radiation and that this re-entry is dependent on a constant supply of nutrients provided by fresh medium changes. The fraction of cells capable of resuming cell cycling is consistent with the surviving fraction of cells in colony assays.

Blotting, Western↗

PubMed1999

Analysis of aberrant methylation of the VHL gene by transgenes, monochromosome transfer, and cell fusion.

Several tumor suppressor genes were shown to be inactivated by a process involving aberrant de novo methylation of their GC-rich promoters which is usually associated with transcriptional repression. The mechanisms underlying this process are poorly understood. In particular this abnormal methylation may be caused and/or maintained by either deficiency of some trans-acting factor(s) or by various malfunctions acting in cis. Here we studied the nature of aberrant methylation of the von Hippel-Lindau (VHL) disease tumor suppressor gene in a human clear cell renal carcinoma cell line, UOK 121, that contains a silent hypermethylated endogenous VHL allele. First, we transfected unmethylated VHL transgenes, driven by the VHL promoter, into UOK 121 cells. Next, to exclude possible position effects that may influence methylation of the introduced VHL genes, we transferred a single chromosome 3, carrying an apparently normal hypomethylated VHL allele into the UOK 121 cells. Finally, we created somatic cell hybrids between UOK 121 and UMRC 6 cells containing a mutant VHL-expressing hypomethylated allele. In these three experiments both the methylation of the VHL promoter and the transcriptional status of the introduced and endogenous VHL alleles remained unchanged. Our results demonstrate that the putative trans-acting factors present in the UOK 121 and UMRC 6 cells are unable to induce changes in methylation pattern of the VHL alleles in all cell lines and hybrids studied. Taken together, the results indicate that cis-specific local features are pivotal in maintaining and perpetuating aberrant methylation of the VHL CpG island. Contribution of some putative trans-acting factors cannot be excluded during a period when the aberrant VHL methylation pattern was first generated.

Adenocarcinoma, Clear Cell↗

PubMed1999

Differential contribution of the ERK and JNK mitogen-activated protein kinase cascades to Ras transformation of HT1080 fibrosarcoma and DLD-1 colon carcinoma cells.

Although an important contribution of ERK and JNK mitogen-activated protein kinase (MAPK) activation in Ras transformation of rodent fibroblasts has been determined, their role in mediating oncogenic Ras transformation of human tumor cells remains to be established. We have utilized the human HT1080 fibrosarcoma and DLD-1 colon carcinoma cell lines, which contain endogenous mutated and oncogenic N- and K-ras alleles, respectively, to address this role. Study of these cells is advantageous over Ras-transformed rodent model cell systems for two key reasons. First, the ras mutations occurred naturally in the progression of the tumors from which the cell lines were derived, rather than due to overexpression of an exogenously introduced gene. Second, although these tumor cells possess defects in multiple genetic loci, it has been established that mutated Ras contributes significantly to the transformed phenotype of these cells. Clonal variant lines of HT1080 and DLD-1 have been isolated which have lost the oncogenic ras allele and exhibit a corresponding impairment in growth transformation in vitro and in vivo. We found that upregulation of Raf/MEK/ERK and JNK correlated with expression of oncogenic Ras in HT1080, but not DLD-1 cells. Furthermore, inhibition of ERK activation in parental HT1080 cells caused the same changes in cell morphology and actin stress fiber organization seen with loss of expression of activated N-Ras(61K). Thus, we suggest that constitutive activation of the Raf/MEK/ERK and JNK pathways is necessary for Ras-induced transformation of HT1080 but not DLD-1 cells. These results emphasize that cell type differences exist in the signaling pathways by which oncogenic Ras causes transformation.

3T3 Cells↗

PubMed1999

Tumor suppression in human skin carcinoma cells by chromosome 15 transfer or thrombospondin-1 overexpression through halted tumor vascularization.

The development of skin carcinomas presently is believed to be correlated with mutations in the p53 tumor suppressor and ras gene as well as with the loss of chromosome 9. We now demonstrate that, in addition, loss of chromosome 15 may be a relevant genetic defect. Reintroduction of an extra copy of chromosome 15, but not chromosome 4, into the human skin carcinoma SCL-I cells, lacking one copy of each chromosome, resulted in tumor suppression after s.c. injection in mice. Transfection with thrombospondin-1 (TSP-1), mapped to 15q15, induced the same tumor suppression without affecting cell proliferation in vitro or in vivo. Halted tumors remained as small cysts encapsulated by surrounding stroma and blood vessels. These cysts were characterized by increased TSP-1 matrix deposition at the tumor/stroma border and a complete lack of tumor vascularization. Coinjection of TSP-1 antisense oligonucleotides drastically reduced TSP-1 expression and almost completely abolished matrix deposition at the tumor/stroma border. As a consequence, the tumor phenotype reverted to a well vascularized, progressively expanding, solid carcinoma indistinguishable from that induced by the untransfected SCL-I cells. Thus, these data strongly suggest TSP-1 as a potential tumor suppressor on chromosome 15. The data further propose an unexpected mechanism of TSP-1-mediated tumor suppression. Instead of interfering with angiogenesis in general, in this system TSP-1 acts as a matrix barrier at the tumor/stroma border, which, by halting tumor vascularization, prevents tumor cell invasion and, thus, tumor expansion.

Animals↗

PubMed1999

Malignant transformation of human diploid fibroblasts and suppression of their anchorage independence by introduction of chromosome 13.

Isolation of cell lines that display various degrees of transformed phenotypes may be very useful to clarify multistep mechanisms of oncogenesis, but malignant transformation of human diploid fibroblasts in culture is a very rare event. We attempted to isolate variously transformed cell lines from human diploid fibroblasts (RB) of a patient with hereditary retinoblastoma. The RB cells exhibited normal karyotypes with the exception of one copy of chromosome 13, which contained a large deletion at the q14-22 region, where the RB1 gene is located. By transfection with SV40 early genes and repeated passage, we succeeded in obtaining SV40-transfected mortal, immortalized, anchorage-independent, and tumorigenic RB cell lines. DNA fingerprinting showed that these cell lines were not contaminants, but derivatives of the original RB cells. The remaining RB1 allele may be wild-type even in the malignant cell lines, because the expression and the LT-binding ability were normal. Furthermore, we did not find any homozygous loss in 16 polymorphic markers located in the 13q14-22 region in the transformed cell lines. However, introduction of a copy of a normal chromosome 13 into the anchorage-independent cell line suppressed its anchorage-independent growth ability. All these data, together with the fact that the RB cells containing the deletion progressed to a tumorigenic state spontaneously, but normal fibroblasts did not, raise the possibility that a new tumor suppressor gene, located at 13q14-22, may play a critical role in neoplastic transformation. We conclude that these RB cell lines provide an excellent system for identification of genes involved in malignant transformation of human cells. Genes Chromosomes Cancer 26:47-53, 1999.

Cell Adhesion↗

PubMed1999

Differential gene expression in tumorigenic and nontumorigenic HeLa x normal human fibroblast hybrid cells.

Fusion of tumorigenic HeLa cells with human skin fibroblasts results in chromosomally stable hybrids that are nontumorigenic and no longer express the HeLa tumor-associated marker intestinal alkaline phosphatase (IAP). Previous studies of spontaneous tumorigenic segregants from the nontumorigenic hybrids implicated the loss of one copy of human fibroblast chromosome 11 in the concomitant reexpression of tumorigenicity. In an attempt to identify genes involved in the control of tumorigenic expression, we performed differential display screening of nontumorigenic hybrid cells and tumorigenic segregants. Subsequent northern blot analyses reproducibly showed 17 differentially expressed genes, eight of which were expressed differentially in the nontumorigenic hybrids and nine of which were expressed differentially in the tumorigenic hybrids. The former were genes for 80K-L protein (a substrate of protein kinase C), AXL/UFO (a receptor tyrosine kinase), insulin-like growth factor binding protein 3, apolipoprotein AI regulatory protein, collagen type I alpha-2 chain, transforming growth factor-beta-induced gene product 3 (BIGH3), pregnancy-specific beta-1-glycoprotein, and fibroblast activation protein alpha. The latter nine genes were genes for serum/glucocorticoid-regulated kinase (SGK; a serine/threonine protein kinase), PTPCAAX1 (a tyrosine phosphatase), CXCR-4 (a G-protein-coupled membrane receptor), L-kynurenine hydrolase, beta-1, 4-galactosyltransferase, keratin 8, keratin 17, and H19 and a novel gene. The differential expression of these genes provided several interesting candidates for regulation of tumorigenic expression, including those involved in signal transduction and the extracellular matrix, cytoskeletal proteins, cell-surface enzyme, and the H19 gene.

Cells, Cultured↗

PubMed1999

Analysis of the pattern of QM expression during mouse development.

QM, a novel gene that was originally identified as a putative tumor suppressor gene, has since been cloned from species encompassing members of the plant, animal, and fungal kingdoms. Sequence comparison indicates that QM has been highly conserved throughout eukaryotic evolution. QM is a member of a multigene family in both mouse and man, is expressed in a broad range of tissues, and is downregulated during adipocyte differentiation. Jif-1, a chicken homolog of QM, has been reported to interact with the protooncogene c-Jun, and to inhibit transactivation of AP-1 regulated promoters in vitro. Furthermore, disruption of the yeast QM homolog is lethal. Although these studies suggest that the QM gene product plays an important role within the normal cell, the precise role of QM has remained elusive. In this study, a thorough analysis of the pattern of QM expression during mouse development was undertaken, using the techniques of whole mount in situ hybridization and whole mount immunohistochemistry, in combination with conventional immunohistochemical analysis of tissue sections. QM is expressed in numerous embryonic tissues, and is differentially expressed throughout the embryo. The cytoplasmic localization of QM is consistent with its reported association with ribosomes, and inconsistent with its previously hypothesized function as a direct modulator of the nuclear protooncogene c-Jun. QM is expressed in the developing epidermis, and is particularly strong within developing limbs. Analysis of embryos of various stages of gestation indicate that QM is downregulated in the surface ectoderm of the embryo as development proceeds. QM protein is not detectable within either nucleated or enucleated red blood cell precursors. QM is strongly expressed within chondrocytes within the transition zone of developing limb cartilage, as well as within differentiated keratinocytes of the suprabasal regions of the epidermis. Furthermore, within both cartilage and skin, there is an inverse relationship between QM expression and proliferative capacity. This pattern of QM expression suggests that this novel gene product may be involved in processes such as posttranslational protein processing which are essential for differentiation of specific tissues during embryogenesis.

Animals↗

PubMed1999

Enhanced expression of glucose transporter GLUT3 in tumorigenic HeLa cell hybrids associated with tumor suppressor dysfunction.

Previous studies on human cell hybrids between HeLa and normal human fibroblasts have indicated that the tumorigenicy may be controlled by a putative tumor suppressor gene on chromosome 11. We previously demonstrated a twofold increase in glucose uptake with a reduced Km by tumorigenic HeLa cell hybrids which expressed a highly glycosylated GLUT1. In this study, we reported that a tumorigenic cell hybrid, CGL4, also expressed a glucose transporter isoform, GLUT3, that was undetectable in nontumorigenic CGL1 cells. The expression of GLUT3 together with GLUT1 of 70 kDa was also evident in three gamma-ray-induced tumorigenic clones isolated from CGL1 cells, while control nontumorigenic irradiated cells expressed 50 kDa GLUT1 alone. In accordance with this, GLUT3 mRNA was specifically expressed in tumorigenic cell hybrids. To examine the role of GLUT3, clones which stably overexpress GLUT3 were developed from both CGL1 and CGL4 cells. In these transfectants, the affinity for 2-deoxyglucose markedly increased, in parallel with the amount of expressed GLUT3 irrespective of its N-glycosylation state. These results suggest that the enhanced GLUT3 expression in HeLa cell hybrids associated with the tumorigenic phenotypes may account for the increased affinity for 2-deoxyglucose. Possible roles of the putative tumor suppressor in control of gene expression and glucose uptake is discussed.

Biological Transport↗

PubMed1998

Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes.

To discover genes involved in von Hippel-Lindau (VHL)-mediated carcinogenesis, we used renal cell carcinoma cell lines stably transfected with wild-type VHL-expressing transgenes. Large-scale RNA differential display technology applied to these cell lines identified several differentially expressed genes, including an alpha carbonic anhydrase gene, termed CA12. The deduced protein sequence was classified as a one-pass transmembrane CA possessing an apparently intact catalytic domain in the extracellular CA module. Reintroduced wild-type VHL strongly inhibited the overexpression of the CA12 gene in the parental renal cell carcinoma cell lines. Similar results were obtained with CA9, encoding another transmembrane CA with an intact catalytic domain. Although both domains of the VHL protein contribute to regulation of CA12 expression, the elongin binding domain alone could effectively regulate CA9 expression. We mapped CA12 and CA9 loci to chromosome bands 15q22 and 17q21.2 respectively, regions prone to amplification in some human cancers. Additional experiments are needed to define the role of CA IX and CA XII enzymes in the regulation of pH in the extracellular microenvironment and its potential impact on cancer cell growth.

Amino Acid Sequence↗

PubMed1998

Germ-line-derived hinge domain p53 mutants have lost apoptotic but not cell cycle arrest functions.

The protein p53 is a critical tumor suppressor, as demonstrated by its frequent mutation in human cancers. Overexpression of the wild-type form of the p53 tumor suppressor gene in human cancer cell lines has been shown to lead to either cell cycle arrest or apoptosis. A study of two Li-Fraumeni syndrome-derived p53 hinge domain mutants shows that both mutants retain the ability to arrest cell growth but are significantly impaired for the induction of apoptosis in human p53-null cell lines. This indicates that the hinge domain may be important in the regulation of p53-dependent apoptosis.

Adolescent↗

PubMed1998

Functional evidence for a nasopharyngeal carcinoma tumor suppressor gene that maps at chromosome 3p21.3.

Nasopharyngeal carcinoma is a malignancy that is prevalent among populations from Southeast Asia. Epidemiological studies indicate that genetic predisposition, Epstein-Barr virus, and environmental conditions may play a role in determining incidence. Molecular studies have implicated a tumor suppressor gene(s) on the short arm of chromosome 3. In this study we provide functional evidence, via monochromosome transfer, for a tumor suppressor gene(s) activity in chromosome 3p21.3.

Animals↗