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

Pathways involving p53 and pRb tumor suppressor genes are frequently deregulated during lung carcinogenesis. Through its location at the interface of these pathways, Mdm2 can modulate the function of both p53 and pRb genes. We have examined here the pattern of expression of Mdm2 in a series of 192 human lung carcinomas of all histological types using both immunohistochemical and Western blot analyses and four distinct antibodies mapping different epitopes onto the Mdm2 protein. Using Immunohistochemistry (IHC), Mdm2 was overexpressed as compared to normal lung in 31% (60 out of 192) of all tumors analysed, whatever their histological types. Western blotting was performed on 28 out of the 192 tumoral samples. Overexpression of p85/90, p74/76 and p57 Mdm2 isoforms was detected in 18% (5 out of 28), 25% (7 out of 28) and 39% (11 out of 28) of the cases respectively. Overall, overexpression of at least one isoform was observed in 14 out of 28 (50%) lung tumors and concomittant overexpression of at least two isoforms in 7 out of 28 (25%) cases. A good concordance (82%) was observed between immunohistochemical and Western blot data. Interestingly, a highly significant inverse relationship was detected between p14(ARF) loss and Mdm2 overexpression either in NSCLC (P=0.0089) or in NE lung tumors (P<0.0001). Furthermore, a Mdm2/p14(ARF) >1 ratio was correlated with a high grade phenotype among NE tumors overexpressing Mdm2 (P=0.0021). Taken together, these data strongly suggest that p14(ARF)and Mdm2 act on common pathway(s) to regulate p53 and/or pRb-dependent or independent functions and that the Mdm2 : p14(ARF) ratio might act as a rheostat in modulating the activity of both proteins.
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PMID:Mdm2 overexpression and p14(ARF) inactivation are two mutually exclusive events in primary human lung tumors. 1196 48

Seventy-one cases of invasive squamous cell carcinoma (ISCC) of the vulva were compared with 18 cases of vulvar intraepithelial neoplasia (VIN) and 21 cases of lichen sclerosus. Ploidy was studied by image analysis, HPV-DNA by PCR, and p53 and pRb by immunohistochemistry. Univariate and multivariate statistical analyses were performed. The mean age of the patients with ISCC was 70.6 years; only 8.5% were < 60 (range, 43-89) years. For the 43 patients with follow-up, FIGO surgical stages were I in 16.2%, II in 48.8%, III in 27.9%, and IV in 6.9%. The 5-year survival was 90% for the patients with curative surgery (vulvectomy and lymphadenectomy) and 32% for those with tumors in stages III to IV. Previous history of nonneoplastic epithelial alterations was recorded in 54%. Vascular invasion was detected in 4.3% and perineural invasion in 21.4%. Inguinal lymph node metastases were present in 34.9% of the cases. Fifty-one (72%) ISCCs were aneuploid, HPV-DNA-16 was detected in 7 (12.3%) cases, overexpression of p53 was found in 40 (56%), and pRb expression was negative in 15 (21.4%). Fifteen cases (80%) of VIN were aneuploid, 5 (27.7%) contained HPV-DNA, 11 (61%) were positive for p53, and all immunoreacted for pRb. All lichen sclerosus cases were diploid, did not contain HPV-DNA, failed to stain for p53, and were positive for pRb. Our study confirmed the prognostic value of conventional pathological features: stage, lymph node metastasis, histological grade, and vascular and perineural invasion; all were statistically significant for survival in the univariate analysis. Also, ploidy was significant in patients with stages I and II tumors. The only significant variable in the multivariate analysis was stage. p53 overexpression appears as a late event in vulvar carcinogenesis, but it may occur before tumor invasion. Lack of pRb expression can occur in vulvar neoplasia, but it does not seem to play any role in the initiation or prognosis of vulvar ISCC.
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PMID:Squamous cell carcinoma of the vulva: study of ploidy, HPV, p53, and pRb. 1209 May 85

We developed the AJBL6 transforming growth factor-beta 1 (TGF-beta1) heterozygous (HT) mouse by mating A/J mice with C57BL/6 TGF-beta1 HT mice that shows increased carcinogen-induced lung lesions with decreased latency to examine progressive events in lung tumorigenesis. Mouse cDNA macroarrays were used to identify cell cycle genes that are differentially regulated in ethyl carbamate-induced lung adenocarcinomas compared with normal lung tissue in AJBL6 TGF-beta1 HT mice using probes that were generated from tissues isolated using laser capture microdissection. While expression of the genes for cyclin D1, CDK4, and E2F1 increased in lung adenocarcinomas relative to normal lung, expression of p15(Ink4b), p16(Ink4a), p21(Cip1), p27(Kip1), p57(Kip2), and pRb genes decreased in comparison. Competitive RT-PCR showed that the levels of cyclin D1 and CDK4 mRNAs were 2- and 3-fold higher, respectively, in lung adenocarcinomas than in normal lung, while the mRNAs for p15(Ink4b), p16(Ink4a), p21(Cip1), p27(Kip1), and pRb were 3- to 4-fold lower in adenocarcinomas than in normal lung, thus validating the macroarray findings. Competitive RT-PCR of microdissected lesions also showed that the levels of cyclin D1 and CDK4 mRNAs increased significantly, while the mRNAs for p15(Ink4b) and p27(Kip1) decreased significantly as lung tumorigenesis progressed. Immunohistochemical staining for cyclin D1 and CDK4 showed staining in >80% of nuclei in adenocarcinomas compared with fewer than 20% of nuclei staining positively in normal lung. In contrast, while >60% of normal lung cells showed immunostaining for p15(Ink4b), p16(Ink4a), p21(Cip1), p27(Kip1), and pRb, staining for these proteins decreased in hyperplasias, adenomas, and adenocarcinomas. These data show that multiple components of the cyclin D1/CDK4/p16(Ink4a)/pRb signaling pathway are frequently altered early in lung lesions of AJBL6 TGF-beta1 HT mice that are induced by ethyl carbamate as a function of progressive lung carcinogenesis, suggesting that components of this pathway may be potential targets for gene therapy.
Carcinogenesis 2002 Jul
PMID:Altered expression of G1/S regulatory genes occurs early and frequently in lung carcinogenesis in transforming growth factor-beta1 heterozygous mice. 1211 81

The human papillomavirus (HPV) oncoprotein E7 is implicated in the etiology of cervical cancer associated with infection by HPV. HPV-positive cells develop resistance to TGF-beta growth inhibitory activity through the inhibition of hypophosphorylation of pRb by papillomavirus type 16 E7 oncoprotein. In this study, we examined whether E7, in addition to its well known effects on pRb, might directly target the Smad proteins that mediate TGF-beta signaling. Here, we show that E7 significantly blocks both Smad transcriptional activity and the ability of TGF-beta to inhibit DNA synthesis. We found that E7 interacts constitutively with Smad2, Smad3, and Smad4. Confocal microscopic studies confirm that E7 and Smads co-localize in vivo. Using a canonical Smad DNA binding sequence, we found that E7 blocks Smad3 binding to its target sequence on DNA. These results suggest that suppression of Smad-mediated signaling by E7 may contribute to HPV-associated carcinogenesis.
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PMID:The human papilloma virus E7 oncoprotein inhibits transforming growth factor-beta signaling by blocking binding of the Smad complex to its target sequence. 1214 12

The retinoblastoma (Rb) gene was the first tumor suppressor gene to be discovered; however, data on the influence of Rb inactivation on endometrial carcinogenesis are scarce. We investigated 46 paired primary human endometrial carcinomas and normal tissues to assess the frequency of loss of heterozygosity (LOH) in Rb and 20 tumor pairs to detect the frequency of p53 LOH. Moreover, expression of the retinoblastoma protein (pRb) was assessed immunohistochemically. Of 44 informative cases 8 showed loss of one allele in at least one Rb marker; Rb LOH frequency thus reached 18%. Two omental metastases of endometrial origin showed a heterogeneity pattern similar to that of the primary tumors. We did not find a significant correlation between Rb LOH and patient age, clinical stage, histological grade or muscle invasion of the tumor. Nevertheless, Rb LOH was demonstrated at early (stage I, 5/27, 18%) and advanced (stages II-IV; 3/9, 33%) clinical stages of the neoplasm, suggesting that LOH at the Rb locus occurs before the clonal expansion of the tumor. There was a significant correlation between Rb LOH and weak/absent pRb expression. We noted a single case of p53 LOH at intron 1, but no tumor showed both alterations simultaneously. Our data suggest that LOH at the Rb locus plays a role in the oncogenesis of a subset of uterine neoplasms and corresponds with the altered expression of the pRb.
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PMID:Loss of heterozygosity of the retinoblastoma gene is correlated with the altered pRb expression in human endometrial cancer. 1246 15

To examine the association of cell cycle regulatory gene inactivation with human cell immortalization, we determined the expression status of INK4a, Rb, and WAF1/ CIP1, in eleven in vitro immortalized human cell lines, including fibroblasts and keratinocytes. Two human papillomavirus type 16 E6 expressing cell lines with telomerase activity, including a fibroblast cell line and a keratinocyte cell line, expressed no detectable p16(INK4a). These cell lines had a hyperphosphorylated pRb and reduced expression of p21(WAF1/CIP1). All of seven fibroblast cell lines immortalized either spontaneously or by (60)Co, X-rays, 4-nitroquinoline 1-oxide or aflatoxin B(1), maintaining their telomeres by the ALT (alternative lengthening of telomeres) pathway, displayed loss of expression of p16(INK4a) and hyperphosphorylation of pRb. Levels of p21(WAF1/CIP1) expression varied among the cell lines. Two fibroblast cell lines that became immortalized following infection with a retrovirus vector encoding human telomerase catalytic subunit (hTERT) cDNA were also accompanied by inactivation of p16(INK4a) and pRb pathways. Acquisition of telomerase activity alone was not sufficient for immortalization of these cell lines. Taken together, all the cell lines including fibroblasts and keratinocytes, with either telomerase activity or the ALT pathway for telomere maintenance showed loss of expression of p16(INK4a) and hyperphosphorylation of pRb. These demonstrate the association of inactivation of both p16(INK4a) and pRb with immortalization of human cells including fibroblasts and epithelial cells and telomerase-positive cells and ALT-positive cells.
Carcinogenesis 2002 Dec
PMID:Association of p16(INK4a) and pRb inactivation with immortalization of human cells. 1250 35

Several studies have suggested the involvement of cutaneous human papillomaviruses (HPVs) in the development of nonmelanoma skin cancers. Here we have characterized the in vitro properties of E7 proteins of three cutaneous HPV types, 10, 20, and 38, which are frequently detected in skin specimens. We show that HPV38 E7 is able to inactivate the tumor suppressor pRb and induces loss of G(1)/S transition control, a key event in carcinogenesis. In contrast, HPV10 and HPV20 E7 proteins do not display these in vitro transforming activities. We also show that the two early proteins E6 and E7 of HPV38 are sufficient to corrupt the cell cycle and senescence programs in primary cells, inducing active and long-lasting proliferation of primary human keratinocytes, the natural host cells. Our study shows that E6 and E7 of this cutaneous HPV type have transforming activity in primary human cells, suggesting a role for HPV38 infection in skin carcinogenesis. In further support of such a role, we detected HPV38 DNA in approximately 50% of nonmelanoma skin cancers, but only in 10% of healthy skin specimens (P < 0.001).
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PMID:The E6 and E7 proteins of the cutaneous human papillomavirus type 38 display transforming properties. 1252 54

Small DNA tumor viruses have evolved different mechanisms to abrogate the function of the retinoblastoma tumor suppressor (pRb). Studies of these viruses have been invaluable in uncovering the central role of the Rb family of pocket proteins in cell cycle control. While the molecular mechanisms by which the viral oncoproteins inactivate the Rb family are still being elucidated, it is clear that targeting of this family is required both for viral replication and for virus-induced transformation of mammalian cells. This review compares and contrasts the approaches DNA tumor viruses have evolved to antagonize Rb family members--ranging from relatively simple equilibrium dissociation of pRb from cellular pRb-binding factors to chaperone-mediated alterations in pocket protein stability and phosphorylation levels. The review will focus on the viral oncoproteins adenovirus E1A, human papillomavirus E7 and the large T antigens of several polyomaviruses. An understanding of these mechanisms may provide further insight into the regulation and functions of Rb family members as well as uncover new targets for the development of novel anti-viral agents, particularly against human papillomavirus, which is a significant cause of human cancer.
Carcinogenesis 2003 Feb
PMID:Mechanisms by which DNA tumor virus oncoproteins target the Rb family of pocket proteins. 1258 63

We have previously demonstrated that the retinoblastoma gene family, Rb, p107 and p130, is differentially expressed during mouse embryogenesis. Here we show that this gene family is coordinately regulated in the mammary luminal epithelium. Expression of Rb, p107 and p130 in the epithelial compartment is low in nulliparous female mice and early stages of pregnancy but is induced at mid-pregnancy and peaks at lactation. During involution p107 expression is lost whereas expression pRb and p130 persist. The induction of this gene family at mid-pregnancy accompanies the expression of beta-casein. However, whereas beta-casein transcripts are confined to the lobuloalveolar compartment, the Rb gene family is expressed both in lobuloalveoli and ducts. The co-expression of the Rb family in the mammary gland may allow functional compensation among these family members. This in turn may explain the recent observations that loss of Rb alone in the mammary gland is inconsequential, whereas overexpression of cyclin D1 or SV40 large T antigen, which can abrogate all members of the pRb protein family, induces mammary gland carcinogenesis.
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PMID:Coordinated expression of Rb gene family in the mammary gland. 1261 34

The functional effect of the interaction of E2F1 and hepatitis B virus X protein (HBx) on the promoter of human p53 gene was studied using chloramphenicol acetyl transferase (CAT) assay. E2F1 activated the p53 promoter through E2F1 binding site. As previously reported, HBx repressed the p53 promoter through E-box. When E2F1 was cotransfected with HBx, E2F1 overcame the repressive effect of HBx on the p53 promoter through the E2F1 site. However, in the thymidine kinase (tk) heterologous promoter system with the E2F1 binding sites, cotransfection of E2F1 and HBx showed a strong synergistic activation. An in vitro interaction assay showed that E2F1 and HBx physically bind with each other. Analyses of the interaction domain with the GAL4 fusion protein showed that the pRb-binding domain of E2F1 was necessary for the functional interaction of these two proteins. Taken together, these results imply the functional inhibitory action of E2F1 on the HBV life cycle and HBV-mediated hepatocellular carcinogenesis (HCC). Therefore, the normal or enhanced function of E2F1 gene would be important in controlling the HBx function in HCC.
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PMID:E2F1 activates the human p53 promoter and overcomes the repressive effect of hepatitis B viral X protein (Hbx) on the p53 promoter. 1262 70


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