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PubMed2002

Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer.

Lung cancer has become the leading cause of cancer death in many economically well-developed countries. Recent molecular biological studies have revealed that overt lung cancers frequently develop through sequential morphological steps, with the accumulation of multiple genetic and epigenetic alterations affecting both tumor suppressor genes and dominant oncogenes. Cell cycle progression needs to be properly regulated, while cells have built-in complex and minute mechanisms such as cell cycle checkpoints to maintain genomic integrity. Genes in the p16INK4A-RB and p14ARF-p53 pathways appear to be a major target for genetic alterations involved in the pathogenesis of lung cancer. Several oncogenes are also known to be altered in lung cancer, leading to the stimulation of autocrine/paracrine loops and activation of multiple signaling pathways. It is widely acknowledged that carcinogens in cigarette smoke are deeply involved in these multiple genetic alterations, mainly through the formation of DNA adducts. A current understanding of the molecular mechanisms of lung cancer pathogenesis and progression is presented in relation to cigarette smoking, an absolute major risk factor for lung cancer development, by reviewing genetic alterations of various tumor suppressor genes and oncogenes thus far identified in lung cancer, with brief summaries of their functions and regulation.

Cell Transformation, Neoplastic↗

PubMed2003

[Changes in the activity of cyclin-kinase complexes governing cell transition from G1 phase to DNA replication phase in E1A + c-Ha-ras transformants transfected with the bcl-2 gene].

The antiproliferative effect of human bcl-2 gene transferred to E1A + c-Ha-ras-transformed rat embryo fibroblasts, which are characterized by the absence of cell cycle checkpoints after damage and by a high proapoptotic sensitivity was studied. Ionizing irradiation, adriamycin treatment, and serum starvation were shown to induce G1/S arrest in E1A + c-Ha-ras-transformants. Bcl-2 antiproliferative effect in E1A + c-Ha-ras-transformants was not associated with alterations in Cdk2, cyclin E and A contents. G1/S arrest following irradiation or serum starvation was accompanied by a decrease in kinase activity associated with cyclin E-cdk2, whereas G1/S arrest in tetraploid subpopulation after adriamycin treatment did not correlate with a decrease in cyclin E-associated kinase activity. Cyclin A-associated kinase activity did not decrease after any used treatment. Transfection of bcl-2 in E1A + c-Ha-ras-transformants resulted in elevated expression of cyclin-cdk complexes inhibitor p21/Waf-1, but not p27/Kip. Damaging agents caused p21/Waf-1 and p27/Kip accumulation, but bcl-2 overexpression did not restore functions of these inhibitors, since p21/Waf-1 and p27/Kip were unable to suppress cyclin-cdk complexes activity after damage. These results suggest that bcl-2 transfection in E1A + c-Ha-ras-transformants is likely to result in irradiation- or serum starvation-induced G1/S arrest accomplished by a selective decrease in cyclin E-associated kinase activity. Adriamycin-induced G1/S arrest seems to be realized via cyclin-cdk complexes activity-independent way involving antiproliferative targets downstream of cyclin E-cdk2 and cyclin A-cdk2 complexes.

Adenovirus E1A Proteins↗

PubMed2005

Ataxia-telangiectasia genes and breast cancer risk in a French family study.

Ataxia-telangiectasia (AT) is a rare autosomal recessive early childhood disorder, characterized by progressive neuronal degeneration, immunological deficiency, radiosensitivity and an increased risk of cancer caused in most cases by mutations in the AT-mutated gene (ATM). Epidemiological studies on AT families have shown that AT heterozygous women have an increased risk of developing breast cancer (BC). The ATM protein plays a central role in the recognition and repair of DNA double-strand breaks and the subsequent activation of cell-cycle checkpoints. Whilst AT is a rare disease, 0.5-1 % of the general population are estimated to be AT mutation carriers, thus any increases in the risks of cancer associated with ATM carrier status are of public health relevance. The main results of our published studies on the risk of BC in 34 French AT families according to heterozygote status, type of ATM mutation and exogenous factors are summarized here. The risk of BC was higher in ATM heterozygous (HetATM) women and did not differ significantly according to the type of ATM mutation (missense vs truncating) carried by the AT family members but appeared associated with the position of some truncating mutations in certain binding domains of the ATM protein. The effect of exogenous factors, such as reproductive life factors and exposure to ionizing radiation, on the risk of BC according to ATM heterozygote status was assessed. There was no evidence for interaction (except for age at first full-term pregnancy). These findings does not appear to justify a separate screening program from that already available to other women with a first-degree relative affected by BC, as their risks have similar amplitude. Chest X-rays did not appear to be a risk factor for BC in our study population. More powerful studies, using data sets pooled from international sources are being set up to confirm these observations.

Ataxia Telangiectasia↗

PubMed1997

Abrogation of G1 arrest after DNA damage is associated with constitutive overexpression of Mdm2, Cdk4, and Irf1 mRNAs in the BALB/c 3T3 A31 variant 1-1 clone.

A search of cell lines showing aberrant cell-cycle checkpoints revealed the lack of gamma-irradiation-induced G1 arrest in the BALB/c 3T3 A31 variant 1-1 (A31-1-1) clone. This clone is well-known for its hypersensitivity to transformation by DNA damaging agents. p53 stabilization and p21 mRNA induction after 8 Gy irradiation were observed, suggesting that the abrogation of G1 arrest occurred in spite of normal p53 and p21 responses by abnormal regulation of other cellular factors. Constitutive overexpression of Mdm2 and Cdk4 mRNAs was found, which might have contributed to the loss of G1 arrest. In addition, overexpression of a growth-suppressive transcription factor, Irf1, a putative key molecule in the p53-independent pathway after DNA damage, was also observed, although the relation to the loss of G1 arrest could not be elucidated.

3T3 Cells↗

PubMed2001

Transcription factors Oct-1 and NF-YA regulate the p53-independent induction of the GADD45 following DNA damage.

The p53-regulated GADD45 gene is one of the important players in cellular response to DNA damage, and probably involved in the control of cell cycle checkpoint, apoptosis and DNA repair. There are both the p53-dependent and -independent pathways that regulate GADD45 induction. Following ionizing radiation, induction of the GADD45 gene is regulated by p53 through the p53-binding motif located in the third intron of the GADD45 gene. In contrast, GADD45 induction by methyl methanesulfonate (MMS), UV radiation (UV), and medium starvation is independent of p53 status although p53 may contribute to these responses. However, the regulatory elements that control the p53-independent induction of GADD45 remain uncertain. In this report, we have performed detailed analyses to characterize the responsive components that are required for the induction of the GADD45 promoter. We have found that the region between -107 and -62 of the GADD45 promoter is crucial for the induction. Sequence analysis indicates that there are two OCT-1 sites and one CAAT box located in this region. Site-directed mutations of both OCT-1 and CAAT motifs substantially abrogate the induction of the GADD45 promoter by DNA damage. In addition, both Oct-1 protein (binding to OCT-1 site) and NF-YA protein (binding to CAAT box) are induced after cell exposure to DNA damaging agents. Moreover, the Electrophoretic Mobility Shift Assay (EMSA) has demonstrated the direct bindings of Oct-1 and NF-YA proteins to their consensus sequences in the GADD45 promoter. Therefore, these results have presented the novel observation that transcription factors Oct-1 and NF-YA participate in the cellular response to DNA damage and are involved in the regulation of stress-inducible genes.

Base Sequence↗

PubMed2004

Xrs2p regulates Mre11p translocation to the nucleus and plays a role in telomere elongation and meiotic recombination.

The Mre11-Rad50-Xrs2 (MRX) protein complex plays pivotal roles in meiotic recombination, repair of damaged DNA, telomere elongation, and cell cycle checkpoint control. Xrs2p is known to be essential for all the functions of the complex, but its role in the complex has not been clearly elucidated. A 32-amino acid region near the C terminus of Xrs2p was identified as an Mre11p-binding site. No more function of Xrs2p than translocation of Mre11p from the cytoplasm to the nucleus is necessary for response to DNA damage. However, domains in Xrs2p located both 49 amino acids upstream and 104 amino acids downstream of the Mre11p binding site are required for meiotic recombination and telomere elongation, respectively, in addition to the 32-amino acid region. These findings demonstrate that Xrs2p acts as a specificity factor that allows the MRX complex to function in meiotic recombination and in telomere elongation.

Alleles↗

PubMed2003

The influence of cyclin D1 (CCND1) 870A>G polymorphism and CCND1-thymidylate synthase (TS) gene-gene interaction on the outcome of childhood acute lymphoblastic leukaemia.

The 870A>G polymorphism in the cyclin D1 (CCND1) gene modulates mRNA splicing, leading to altered protein that may affect the regulation of the G1/S cell-cycle checkpoint. This polymorphism has been reported to influence susceptibility to and progression of several malignancies. Furthermore, the change of retinoblastoma protein regulation mediated by CCND1 may play a role in the development of methotrexate (MTX) resistance via an associated higher activity of enzymes that are inhibited by MTX. This study shows that children with acute lymphoblastic leukaemia (ALL) who are homozygous for the CCND1 A variant have a lower probability of event-free survival (P = 0.006) compared to carriers of the G variant. A significant result is retained in the presence of other prognostic factors. This impact is even more apparent in individuals who are also homozygous for thymidylate synthase (TS) triple repeat (P < 0.00005), which has previously been shown to influence the outcome of childhood ALL.

Child↗

PubMed2004

The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4.

Ataxia-oculomotor apraxia 1 (AOA1) is an autosomal recessive neurodegenerative disease that is reminiscent of ataxia-telangiectasia (A-T). AOA1 is caused by mutations in the gene encoding aprataxin, a protein whose physiological function is currently unknown. We report here that, in contrast to A-T, AOA1 cell lines exhibit neither radioresistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of A-T. In addition, AOA1 primary fibroblasts exhibit only mild sensitivity to ionising radiation, hydrogen peroxide, and methyl methanesulphonate (MMS). Strikingly, however, aprataxin physically interacts in vitro and in vivo with the DNA strand break repair proteins XRCC1 and XRCC4. Aprataxin possesses a divergent forkhead associated (FHA) domain that closely resembles the FHA domain present in polynucleotide kinase, and appears to mediate the interactions with CK2-phosphorylated XRCC1 and XRCC4 through this domain. Aprataxin is therefore physically associated with both the DNA single-strand and double-strand break repair machinery, raising the possibility that AOA1 is a novel DNA damage response-defective disease.

Apraxias↗

PubMed2006

Selective intratumoral amplification of an antiangiogenic vector by an oncolytic virus produces enhanced antivascular and anti-tumor efficacy.

The development of effective cancer therapy will require the simultaneous targeting of multiple steps in tumor development. We have previously described an antiangiogenic gene therapy vector, Ad Flk1-Fc, which expresses a soluble VEGF receptor capable of inhibiting tumor angiogenesis and growth. We have also described an oncolytic virus, dl922/947, whose replication and subsequent cytotoxicity are restricted to cancer cells with a loss of the G1-S cell cycle checkpoint. Here we have optimized methods for combining these therapies, yielding significantly greater anti-tumor effects than the respective monotherapies. In cultured tumor lines, co-infection with both Ad Flk1-Fc and dl922/947 allowed replication and repackaging of the replication-deficient Ad Flk1-Fc and enhanced soluble VEGF receptor expression. Similar repackaging and increased gene expression were demonstrated in vivo using bioluminescence imaging studies. Finally, coadministration of these therapeutic viral therapies in vivo produced significantly enhanced anti-tumor effects in colon HCT 116 and prostate PC-3 xenografts in mice. This increased therapeutic benefit correlated with replication of Ad Flk1-Fc viral genomes, increased intratumoral levels of Flk1-Fc protein, and decreased microvessel density, consistent with enhanced antiangiogenic activity.

Adenocarcinoma↗

PubMed2001

Molecular analysis of the 9p21 locus and p53 genes in Ewing family tumors.

SUMMARY: The EWS-ETS rearrangements, and their respective fusion gene products, are specifically associated with histopathologically Ewing family tumors (EFT). These translocations are implicated in generating malignant transformation of EFT, but the presence of additional genetic alterations must be considered in the pathogenesis of such tumors. We analyzed 26 samples (biopsies and/or nude mice xenotransplants) collected from 19 patients with an EFT to determine whether molecular and cytogenetic alterations of the G(1)/S checkpoint genes are implicated in the pathogenesis of EFT. We found inactivating p53 mutations in three (16%) cases, which correlated with a loss of p21(WAF1/Cip1) expression and with a monosomy of chromosome 17 in two cases. Homozygous deletion of the p16(INK4A)/p14(ARF) gene was detected in four (21%) cases, three with codeletion of the p15(INK4B) gene and with chromosome 9 abnormalities. In all of these cases, expression of the implicated genes was absent. Hypermethylation of the p16(INK4A) and p15(INK4B) genes was detected in two (10%) and three (16%) cases, respectively, and was correlated with a low level of gene expression. Neither cyclin D1, nor MDM2 and CDK4 amplification was observed. Kaplan-Meier analysis showed that patients with tumors carrying homozygous deletion of the 9p21 locus, or point mutations of the p53 gene, had poorer outcomes than those without these molecular alterations (p = 0.005). In conclusion, 58% (11 of 19) of the analyzed patients showed genetic or epigenetic alterations in either the 9p21 locus or p53 tumor suppressor genes, defining a subgroup of patients with poor clinical outcome. This fact points to an important role of the G(1)/S cell cycle checkpoint dysregulation in the pathogenesis of EFT.

Adolescent↗

PubMed2005

Gene expression and apoptosis induction in p53-heterozygous irradiated mice.

The role of the p53-genetic background in the expression of genes involved in either cell cycle checkpoint activation or apoptosis was evaluated in p53+/+ and p53+/- mouse strains at both basal levels and after DNA-induced damage. The spleen, colon, kidneys, lungs and liver of both strains were harvested from untreated animals and from mice exposed to 7.5 Gy of X-rays and sacrificed after 5 h. No significant differences were observed in the basal levels of p53 protein, CDKN1A and bax mRNA and spontaneous apoptosis, neither among the different organs within the same strain, nor between the same organ in the p53+/+ and p53+/- strains. After X-ray exposure, p53-dependent regulation was strikingly tissue-specific. In wild-type irradiated mice, p53 protein level increased after radiation treatment in all the organs analysed, whereas both CDKN1A and bax genes transcription increased in the spleen, colon and lungs, as assessed by means of quantitative RT-PCR. In p53+/- irradiated mice, on the contrary, a significant p53 induction was detected only in the spleen, while CDKN1A and bax genes levels increased in the spleen, colon and lungs, revealing the existence of different mechanisms of gene regulation in different organs. Apoptosis induction was observed in the spleen and colon of both strains, even if to lower extent in p53+/- mice compared to p53+/+ animals. In conclusion, in the spleen and colon, target gene transcription and apoptosis may be related to p53 genotype after DNA damage-induction. Moreover, our findings highlight the selectivity of p53 in transactivation following DNA damage in vivo, resulting in tissue-specific responses.

Animals↗

PubMedDate not supplied

DNA methylation of CHFR is not a predictor of the response to docetaxel and paclitaxel in advanced and recurrent gastric cancer.

BACKGROUND: Cell cycle checkpoint dysfunction is often associated with sensitivity to chemotherapeutic agents. In this study, the question of whether DNA methylation of CHFR, a mitotic checkpoint gene, can predict the response of advanced and recurrent gastric cancers (GCs) to docetaxel or paclitaxel was examined. MATERIALS AND METHODS: In a retrospective study, 41 patients with GC treated with paclitaxel alone (n=12) or a combination of docetaxel and S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine, potassium oxonate) (n=29) were studied. The DNA methylation status of the CHFR gene was examined by combined bisulfite restriction analysis of DNAs from 41 GC tissues and the methylation status was compared to their sensitivity to chemotherapy. The levels of CHFR mRNA were measured by quantitative reverse transcription-PCR. RESULTS: DNA methylation of CHFR was found in 15 (36.6%) out of the 41 GC samples and the levels of CHFR mRNA were associated with the methylation status of CHFR (p = 0.034). In 41 samples of corresponding non-neoplastic mucosae, no DNA methylation of CHFR was detected. Among 12 patients treated with paclitaxel alone, only 1 (20.0%) of the 5 patients with CHFR methylation had a partial response (PR) to paclitaxel, whereas 3 (42.9%) of the 7 patients without CHFR methylation had a PR to paclitaxel (p = 0.836). In 29 patients treated with a combination of S-1 and docetaxel, there was no clear association between the CHFR methylation status and response to chemotherapy (p = 0.092). CONCLUSION: We conclude that the DNA methylation of CHFR alone cannot predict the response of advanced and recurrent GC to docetaxel or paclitaxel. Both paclitaxel and docetaxel may be effective for treatment of GC even if CHFR is expressed.

Adult↗

PubMed2005

Spindle abnormalities in normally developing and arrested human preimplantation embryos in vitro identified by confocal laser scanning microscopy.

BACKGROUND: Despite recent technical improvements, many human preimplantation embryos fail to develop to the blastocyst stage or implant after transfer to the uterus. A possible cause for this developmental arrest is the high incidence of nuclear and postzygotic chromosomal abnormalities observed during cleavage, including chaotic chromosome complements, suggestive of defects in mitotic chromosomal segregation. The underlying mechanisms are largely unknown, but similarities with chromosome instability in human cancers led to the proposal that cell cycle checkpoints may not operate at these early stages. METHODS: To investigate this and to examine whether spindle abnormalities contribute to chromosome malsegregation, we have used fluorescence and confocal laser scanning microscopy, following immunolabelling with antibodies specific for alpha-tubulin, gamma-tubulin, or acetylated tubulin, combined with a DNA fluorochrome to visualize nuclei, spindle and chromosome configurations in normal and arrested human embryos, from cleavage to blastocyst stages. RESULTS: In addition to frequent interphase nuclear abnormalities, we identify for the first time various spindle abnormalities including abnormal shape and chromosome loss and multipolar spindles at cleavage and blastocyst stages. CONCLUSIONS: We propose that a major pathway leading to postzygotic chromosomal abnormalities is the formation of binucleate blastomeres with two centrosomes which result either in a bipolar spindle and division to two tetraploid blastomeres, or in a multipolar spindle, chromosome malsegregation and chromosomal chaos.

Acetylation↗

PubMed2004

Caenorhabditis elegans ABL-1 antagonizes p53-mediated germline apoptosis after ionizing irradiation.

c-Abl, a conserved nonreceptor tyrosine kinase, integrates genotoxic stress responses, acting as a transducer of both pro- and antiapoptotic effector pathways. Nuclear c-Abl seems to interact with the p53 homolog p73 to elicit apoptosis. Although several observations suggest that cytoplasmic localization of c-Abl is required for antiapoptotic function, the signals that mediate its antiapoptotic effect are largely unknown. Here we show that worms carrying an abl-1 deletion allele, abl-1(ok171), are specifically hypersensitive to radiation-induced apoptosis in the Caenorhabditis elegans germ line. Our findings delineate an apoptotic pathway antagonized by ABL-1, which requires sequentially the cell cycle checkpoint genes clk-2, hus-1 and mrt-2; the C. elegans p53 homolog, cep-1; and the genes encoding the components of the conserved apoptotic machinery, ced-3, ced-9 and egl-1. ABL-1 does not antagonize germline apoptosis induced by the DNA-alkylating agent ethylnitrosourea. Furthermore, worms treated with the c-Abl inhibitor STI-571 (Gleevec; used in human cancer therapy), two newly synthesized STI-571 variants or PD166326 had a phenotype similar to that generated by abl-1(ok171). These studies indicate that ABL-1 distinguishes proapoptotic signals triggered by two different DNA-damaging agents and suggest that C. elegans might provide tissue models for development of anticancer drugs.

Amino Acid Sequence↗

PubMed2001

Expression, purification, and biophysical characterization of the BRCT domain of human DNA ligase IIIalpha.

The C-terminal regions of several DNA repair and cell cycle checkpoint proteins are homologous to the breast-cancer-associated BRCA-1 protein C-terminal region. These regions, known as BRCT domains, have been found to mediate important protein-protein interactions. We produced the BRCT domain of DNA ligase IIIalpha (L3[86]) for biophysical and structural characterization. A glutathione S-transferase (GST) fusion with the L3[86] domain (residues 837-922 of ligase IIIalpha) was expressed in Escherichia coli and purified by glutathione affinity chromatography. The GST fusion protein was removed by thrombin digestion and further purification steps. Using this method, (15)N-labeled and (13)C/(15)N-double-labeled L3[86] proteins were prepared to enable a full determination of structure and dynamics using heteronuclear NMR spectroscopy. To obtain evidence of binding activity to the distal BRCT of the repair protein XRCC1 (X1BRCTb), as well as to provide insight into the interaction between these two BRCT binding partners, the corresponding BRCT heterocomplexes were also prepared and studied. Changes in the secondary structures (amount of helix and sheet components) of the two constituents were not observed upon complex formation. However, the melting temperature of the complex was significantly higher relative to the values obtained for the L3[86] or X1BRCTb proteins alone. This increased thermostability imparted by the interaction between the two BRCT domains may explain why cells require XRCC1 to maintain ligase IIIalpha activity.

Amino Acid Sequence↗

PubMed2000

Genome instability in human tumorigenesis: microphotometry of interphase nuclei and pathologic mitoses reveals dysplasia.

Tumorigenesis goes with genome instability comprising point mutations and gross chromosome aberrations due to defective DNA repair mechanisms and multiple overrun of cell cycle checkpoints. Pathologic mitoses (CDFs) occur in human precancers and cancers and were detected by nuclear DNAs deviating more or less than 0.5 c from 4.0 c values. Abundant CDFs were recorded above 4.5 c threshold in lesions of the uterine cervix and the stomach. Low-grade dysplasias and well differentiated carcinomas showed 3%-10% CDFs, high-grade dysplasias 30%-44% CDFs in total divisions. Poorly differentiated cancers comprised some 50% CDFs. Most telophase CDFs showed asymmetric morphology and unbalanced DNA content in their corresponding "halves". CDFs precede DNA aneuploidy of interphase nuclei not only in precancers, but also in cancer. Chromatin bridges and lagging chromosomes suggest that unbalanced telophases are caused by somatic nondisjunction. Tumour progression from low-grade to high-grade dysplasia and cancer is characterised by recurrent shifts from 2 c to 4 c interphase nuclei and a remarkable increase in the 5 c exceeding rate. Clonal selection is the gateway in tumorigenesis for aberrant karyotypes.

Breast Neoplasms↗

PubMed2005

Association of polymorphisms in the cyclin D1 and XPD genes and susceptibility to cancers of the upper aero-digestive tract.

DNA repair enzyme genetic polymorphisms have been postulated to increase the risk of certain cancers in the presence of tobacco carcinogen exposures. The XPD protein is an important component of the TFIIH transcription factor complex. XPD genetic polymorphisms resulting in amino acids substitutions may lead to alterations in TFIIH helicase activity, resulting in repair and transcription defects. Cyclin D1 is a key regulatory protein for the transition of cells from the G(1)-S cell cycle phase. The CCND1 G870A polymorphism has been reported to enhance alternate splicing of a stable mRNA variant, which may result in the bypass of the G(1)/S cell cycle checkpoint. In this study, XPD G23591A (Asp312Asn) and A35931C (Lys751Gln) polymorphisms and the CCND1 G870A splice variant frequencies were determined in 273 upper aero-digestive tract cancer cases and 269 controls. The XPD Asp312Asn variant frequency was significantly different among cases and controls and conferred an odds ratio (OR) of 1.3 (95% CI 1.0-1.8). However, individuals with the CCND1 G870A and XPD Lys751Gln variants had higher age adjusted ORs of 3.2 (95% CI 2.2-4.6) and 2.2 (95% CI 1.5-3.2), respectively. Furthermore, a significant gene-gene interaction was observed among cases with at least two variant alleles for both CCND1 and XPD genes [OR 7.09 (95% CI 4.03-12.5)]. Smokers with a combination of at least one variant allele of both CCND1 and XPD genes also had an elevated risk as compared to nonsmokers. This is the first study to suggest an associative interaction between XPD and CCND1 genetic polymorphisms, tobacco exposure, and cancer risk.

Alternative Splicing↗

PubMed2001

Expression of molecular mediators of apoptosis and their role in the pathogenesis of lower-extremity varicose veins.

PURPOSE: In an earlier study, we observed a significant decrease in apoptosis in varicose veins, as compared with healthy veins, indicating that deregulated apoptosis plays a role in the pathogenesis of varicosities. In addition, significant differences were noted in the expression and subcellular localization of the cell cycle regulatory protein, cyclin D1 in varix tissues, as compared with controls. Because cell cycle checkpoint controls are linked to the signaling and execution of apoptotic cascades, we examined the expression of bcl-2 family members bax and bcl-x, known molecular mediators of apoptosis, and that of poly (ADP-ribose) polymerase (PARP), a downstream substrate of DNA cleavage. METHODS: Twenty varicose vein specimens were retrieved from 20 patients (10 men, 10 women; mean age, 53.6 +/- 4.7 years) undergoing lower-extremity varicose vein excision. Healthy greater saphenous vein segments (n = 27) were obtained from 27 patients (14 men, 13 women; mean age, 59.5 +/- 2.4 years) undergoing infrainguinal arterial bypass grafting surgery. All tissues were distal portions. As per CEAP classification for chronic lower-extremity venous disease, most of the patients were in class 2 for clinical signs (n = 11); some patients were in class 3 (n = 4) or class 4 (n = 4), and only one patient was in class 5. Five 5-microm thick sections from formalin-fixed, paraffin-embedded specimens were used as a means of immunohistochemically localizing the expression of bax, bcl-x, and PARP, and 10 random high-power fields per section were evaluated by two independent reviewers blinded to the clinical findings. Statistical analyses were conducted by means of chi(2), analysis of variance, Student and Fisher exact t tests with StatView software. RESULTS: Immunoreactivity to pro-apoptotic bax was significantly higher in the normal veins (P <.001). Cytoplasmic expression of bcl-x was prominent in the cells of the vasa vasorum in both varicose and healthy veins. PARP expression was diminished in the varicose vein group, with 2.8 +/- 0.7 (P =.01) and 1.4 +/- 0.5 (P =.05) cells per high-power field in the intima and media, respectively. Neither bax nor PARP was noted in the adventitia of varicose veins, although their expression was detected in this layer of the control group (P <.001). CONCLUSION: The entry of smooth muscle cells into the apoptotic pathway may be regulated by the induction of bax in this model, because there is significant presence of this pro-apoptotic protein in healthy veins. Both bax and PARP are downregulated in varicose veins, as compared with healthy veins, and this may play a significant role in the pathogenesis of varicose veins.

Apoptosis↗