Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adenovirus E1A gene product, the simian virus 40 large tumor antigen, and the human papillomavirus E7 protein share a short amino acid sequence that constitutes a domain required for the transforming activity of these proteins. These sequences are also required for these proteins to bind to the retinoblastoma gene product (pRb). Recent experiments have shown that E1A can dissociate complexes containing the transcription factor E2F bound to pRb, dependent on this conserved sequence element. We now show that the E7 protein and the simian virus 40 large tumor antigen can dissociate the E2F-pRb complex, dependent on this conserved sequence element. We also find that the E2F-pRb complex is absent in various human cervical carcinoma cell lines that either express the E7 protein or harbor an RB1 mutation, suggesting that the loss of the E2F-pRb interaction may be an important aspect in human cervical carcinogenesis. We suggest that the ability of E1A, the simian virus 40 large tumor antigen, and E7 to dissociate the E2F-pRb complex may be a common activity of these viral proteins that has evolved to stimulate quiescent cells into a proliferating state so that viral replication can proceed efficiently. In circumstances in which a lytic infection does not proceed, the consequence of this action may be to initiate the oncogenic process in a manner analogous to the mutation of the RB1 gene.
 ...
PMID:Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product. 131 11

It has been reported that the p53 gene mediates an ionizing radiation-induced G1 arrest in mammalian cells. To further characterize this important phenomenon, a panel of seven human diploid fibroblast cell strains and 14 human tumor cell lines from a variety of sources with both wild-type and mutant p53 status were assayed for their susceptibility to G1 arrest after gamma-ray irradiation by a continuous labeling [3H]thymidine incorporation technique. An irreversible G1-block involving 20-70% of the cell population was observed in diploid fibroblasts irradiated with 4 Gy. The block was abolished by transfection with the Human Papilloma Virus E6 gene and in an ataxia telangiectasia (AT) cell line, indicating a role for the AT and p53 genes respectively in this process. In contrast to wild-type normal fibroblast cell strains, the G1-block in all tumor cell lines was significantly reduced, irrespective of their p53 status. None of the nine human tumor cell lines with mutant p53 genes showed a significant G1-block following irradiation with 4 Gy. Among the five tumor cell lines expressing wild-type p53, two showed no apparent G1-block. The remaining three showed a G1-block involving only 8-15% of the cell population, a block much smaller in magnitude than that seen in diploid fibroblasts. Finally, a diploid fibroblast cell strain and a tumor cell line, both showing a normal p53 and p21/WAF1 expression pattern, were examined for pRb phosphorylation before and after irradiation. The diploid fibroblast cell strain showed a significant G1-arrest and a clear inhibition of pRb phosphorylation by irradiation whereas the tumor cells showed no G1-arrest and no inhibition of pRb phosphorylation. These results suggest that (1) multiple genetic factors may modulate the occurrence and magnitude of the G1-arrest induced by exposure to ionizing radiation, (2) the capacity for p53 to mediate a radiation-induced G1 arrest is significantly reduced in tumor cells, (3) the disruption of G1-block modulating factor(s) other than p53 may be an important step in carcinogenesis.
 ...
PMID:Diminished capacity for p53 in mediating a radiation-induced G1 arrest in established human tumor cell lines. 747 18

Human papillomaviruses (HPVs) contribute to the development of benign and malignant cervical cancer; however, the exact role of papillomaviruses in the multistage carcinogenesis process is unclear. The development of HPV-immortalized cervical and foreskin cell lines represents a useful model for studying the role of HPVs in cervical cancer. Studies with these cells show that HPV genes regulate epithelial cell growth and differentiation. Transfection of HPV types associated with invasive cervical cancer results in immortalization of human epithelial cells, whereas HPVs not associated with cancer are ineffective. The combination of E6 and E7 genes, which are normally retained and expressed in cervical carcinomas, is sufficient for immortalization; however, the E7 gene alone induces immortality less efficiently. Although the immortalized cells actively express HPV oncoproteins observed in cervical cancer, after injection of immortal cells into nude mice, tumors are rare, having been reported only for HPV-18. Immortalized cells are resistant to terminal differentiation; in fact, HPVs may contribute to the carcinogenic process by uncoupling the processes of cell growth and differentiation. Host regulation of viral genes also is important in the malignant process. Endogenous cytokines modify HPV gene expression and influence the pathogenesis of HPV infection in the cervix. HPV gene expression is regulated by cellular transcriptional activators and repressors. This normal regulation is altered by viral integration. HPVs become integrated preferentially at chromosomal regions near fragile sites and protooncogenes. In fact, immortality is associated with induction of structural rearrangements frequently affecting HPV integration sites. Structural and numerical alterations nonrandomly involve chromosomes 1, 11, 19, and 20, with chromosome 1 alteration being the most predominant. Wild-type functions of Rb and p53 are necessary to control normal cell growth, and mutation or loss of these suppressor genes often contributes to cancer development. In HPV-containing carcinomas, pRb and p53 were wild type. However, in carcinomas lacking HPV, both suppressor genes were mutated. Functional inactivation of these tumor suppressor genes by HPV oncoproteins E6 and E7 may explain this difference. Treatment of HPV-immortalized cells with ras or a subfragment of herpes simplex virus (HSV) of HPV-immortalized cells resulted in locally invasive carcinomas when the cells were implanted subcutaneously in nude mice. These experiments indicate that HPV integration and expression are insufficient for malignancy but that HPVs do participate in the multistep development of cancer.
 ...
PMID:Cellular and molecular alterations in human epithelial cells transformed by recombinant human papillomavirus DNA. 839 44

Human papillomavirus type 16 is a strong ethiologic agent of tumor development in human mucous epithelia such as uterine cervix. The virus two early genes, E6 and E7, have been characterized to be oncogenes that transform various cells and cell lines in vitro. Extensive analyses of E6 and E7 proteins revealed that these two oncoproteins interacted with cellular tumor suppressors, p53 and pRb, respectively. Thus, oncogenic potentials of the E6/E7-genes could be explained in part by the consequence of crosstalk of E6/E7-proteins and the cell cycle regulators. Furthermore, telomerase activation that protects telomere erosion appeared to by necessary for HPV16-oncogenesis and was demonstrated in HPV16-immortalized human epithelial cell lines. This line of evidence now enabled us to describe, but not fully, a scheme of an earlier process of human carcinogenesis induced by this virus type.
 ...
PMID:[Human papillomavirus type 16-gene functions relevant to molecular human carcinogenesis]. 853 55

Each human papillomavirus (HPV) type is genotypically distinct and infects epithelial cells at unique anatomic sites. Among the HPV types described, a subgroup is associated with genital disease and a subset of these is found in 90% of genital cancers. Although in benign infections the viral genome is present as an episome, in cancers it is integrated. The integration event invariably results in the expression of two viral proteins, E6 and E7. These two proteins are capable of transforming cells individually and cooperate to immortalize primary human epithelial cells. Molecular analysis has revealed that the E6 protein encoded by the HPV "high risk" types prevalent in cancers forms a tripartite complex with the p53 tumor suppressor protein and a cellular protein termed E6-AP, resulting in the degradation of p53. The E7 protein encoded by "high-risk" HPV types shows high-affinity association with the retinoblastoma tumor suppressor, pRb. The E7 protein associates also with other cellular factors known to play a role in cell cycle regulation. This review discusses the evidence, molecular and biological, in vitro and in vivo, supporting a direct role for the "high-risk" HPV type encoded E6 and E7 proteins in cervical carcinogenesis.
 ...
PMID:The oncogenic role of human papillomavirus proteins. 910 94

The p16 (MTS1) tumour-suppressor gene is a cyclin-dependent kinase (cdk) inhibitor that decelerates the cell cycle by inactivating the cdks that phosphorylate the retinoblastoma tumour-suppressor gene (Rb) protein (pRb). In cervical cancers, pRb is inactivated by the HPV E7 oncoprotein or by mutations. The hypothesis of earlier reports was that the disruption of the p16/cdk-cyclin/Rb cascade is essential for malignant cervical transformation/carcinogenesis. We previously established in vitro model systems of cervical cancer representing four steps of oncogenic progression initiated by the two most common oncogenic HPVs in ectocervical and endocervical epithelial cells. This report used these systems to investigate the role of p16 in cervical cancers. A dramatic enhancement of the p16 RNA level was observed after immortalization by HPV 16 or 18. Furthermore, the p16 protein was newly observed following immortalization. However, no further changes were found for RNA or protein levels after serum selection or malignant transformation. For three cervical carcinoma cell lines, similar high levels of p16 expression were seen. Point mutations or homozygous deletions of p16 were not observed in the in vitro systems or in clinical specimens. These results suggest that the inactivation of the p16/cdk-cyclin/Rb cascade does not occur during malignant transformation but occurs during the immortalization by HPV in HPV-harbouring premalignant lesions, the in situ equivalent of immortalized cells. Also suggested is that p16 has no role in the specific malignant transformation step from immortal premalignant lesions during the carcinogenesis of HPV-initiated cervical cancers.
 ...
PMID:Induction of p16 during immortalization by HPV 16 and 18 and not during malignant transformation. 916 31

High-risk human papillomavirus type 16 (HPV-16) and HPV-18 are associated with the majority of human cervical carcinomas, and two viral genes, HPV E6 and E7, are commonly found to be expressed in these cancers. The presence of HPV-16 E7 is sufficient to induce epidermal hyperplasia and epithelial tumors in transgenic mice. In this study, we have performed experiments in transgenic mice to determine which domains of E7 contribute to these in vivo properties. The human keratin 14 promoter was used to direct expression of mutant E7 genes to stratified squamous epithelia in mice. The E7 mutants chosen had either an in-frame deletion in the conserved region 2 (CR2) domain, which is required for binding of the retinoblastoma tumor suppressor protein (pRb) and pRb-like proteins, or an in-frame deletion in the E7 CR1 domain. The CR1 domain contributes to cellular transformation at a level other than pRb binding. Four lines of animals transgenic for an HPV-16 E7 harboring a CR1 deletion and five lines harboring a CR2 deletion were generated and were observed for overt and histological phenotypes. A detailed time course analysis was performed to monitor acute effects of wild-type versus mutant E7 on the epidermis, a site of high-level expression. In the transgenic mice with the wild-type E7 gene, age-dependent expression of HPV-16 E7 correlated with the severity of epidermal hyperplasia. Similar age-dependent patterns of expression of the mutant E7 genes failed to result in any phenotypes. In addition, the transgenic mice with a mutant E7 gene did not develop tumors. These experiments indicate that binding and inactivation of pRb and pRb-like proteins through the CR2 domain of E7 are necessary for induction of epidermal hyperplasia and carcinogenesis in mouse skin and also suggest a role for the CR1 domain in the induction of these phenotypes through as-yet-uncharacterized mechanisms.
 ...
PMID:Both conserved region 1 (CR1) and CR2 of the human papillomavirus type 16 E7 oncogene are required for induction of epidermal hyperplasia and tumor formation in transgenic mice. 922 80

Human papillomavirus (HPV) deoxyribonucleic acid (DNA) has been originally detected in urothelial carcinomas of the bladder in immunocompromized patients. Studies from the general population showed a variable incidence of high risk HPV DNA which ranged from 2.5% to 81%, with HPV 16 DNA occurring more frequently. HPV DNA was detected in both papillary and invasive cancers, although in our experience the overall incidence was low. Most HPV positive cases were of high grade and stage with significant reduced survival or increased recurrence rate after transurethral resection. These results indicate an additional prognostic value of viral infection in bladder cancer. In addition, molecular studies suggest that the HPV related oncoproteins E6 and E7 play a role in bladder carcinogenesis via inactivation and/or degradation of p53 and pRb suppressor gene-associated proteins. The purpose of this review is to provide a brief summary of what is known about HPV and bladder cancer, and to address issues germane to the translation of this information to patient management.
 ...
PMID:Human papillomavirus and bladder cancer. 930 45

To better understand the roles of p53 and cell cycle-regulating protein alterations in human esophageal carcinogenesis, we investigated immunohistochemically the distribution patterns of Waf1p21, pRb, p16 and p53 in 22 cases of surgically resected esophageal cancer as well as in the neighboring non-cancerous squamous epithelia. Waf1p21 protein was detected in 13 of the 20 cases of well-differentiated squamous-cell carcinoma (SCC), where the Waf1p21-positive cells were located mainly in the interior layers of the cancer nests. Conversely, p53-positive cells were found mostly in the peripheral layers. Cells containing both Waf1p21- and p53-positive immunostaining were not observed in a double-immunostaining experiment. p16 was detected in both the nucleus and cytoplasm in 3 of the 22 cases of SCC. All of these p16-positive cancers showed an absence of pRb immunostaining; this result is consistent with the idea that expression of p16 is regulated negatively by pRb. Eleven of the 22 esophageal SCCs (50%) showed extensive pRb immunostaining cells, and the remaining 11 cases displayed a few pRb-positive cells or an absence of pRb immunostaining. In a majority of the morphologically normal squamous-cell epithelia samples, immunostaining of Waf1p21 and pRb was found in most of the cells in the parabasal layers (proliferation compartment), where PCNA-positive cells also resided. In the pre-cancerous lesions, Waf1p21 and pRb were detected in cells surrounding the top of the lesioned region, p16-positive cells were scattered in the basal cell hyperplastic and dysplastic lesions and p53-positive cells existed in 2 distinct patterns: "scattered" and "focal".
 ...
PMID:Immunohistochemical studies on Waf1p21, p16, pRb and p53 in human esophageal carcinomas and neighboring epithelia from a high-risk area in northern China. 931 88

Cyclin D1 plays a key role in the regulation of the G1/S transition through the cell cycle. Deregulation of cyclin D1, most often leading to overexpression of the gene, has been reported in many tumor types. It has been suggested that cyclin D1 overexpression could be an alternative mechanism for pRb inactivation. We have previously found Rb gene mutations in 55% of malignant thyroid tumors. In the present study, we examined the cyclin D1 gene expression and amplification in 24 tumor samples (two of them are benign goiters) randomly selected from the same series of thyroid tumors, to see whether cyclin D1 overexpression is present in those specimens without Rb gene mutations. We found a four- to fivefold increase in cyclin D1 expression in 7 of 22 thyroid carcinomas as compared with that in benign nodular goiters. Six of them were found in carcinomas without Rb gene mutations. Among the remaining 15 thyroid carcinoma samples, 11 were found previously to have Rb gene mutations. The association between increased cyclin D1 expression and absence of Rb mutation is statistically significant (p < 0.05). We found no evidence of the cyclin D1 gene amplification or rearrangement to account for such an increase in cyclin D1 expression. We conclude that cyclin D1 overexpression may be relevant to thyroid carcinogenesis. Two mechanisms may be involved in the inactivation of pRb: one is through Rb gene mutations, and the other is by cyclin D1 overexpression.
 ...
PMID:Inverse association between cyclin D1 overexpression and retinoblastoma gene mutation in thyroid carcinomas. 966 46


1 2 3 4 5 6 7 8 9 10 Next >>