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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

B cell translocation gene 2 (BTG2) is a p53 target that negatively regulates cell cycle progression in response to DNA damage and other stress. The objective of this study was to examine the expression, regulation and tumor suppressor properties of BTG2 in prostate cells. By immunohistochemistry BTG2 protein was detected in approximately 50% of basal cells in benign glands from the peripheral zone of the human prostate. BTG2 was expressed in all hyperproliferative atrophic peripheral zone lesions examined (simple atrophy, post-atrophic hyperplasia and proliferative inflammatory atrophy), but was undetectable or detectable at very low levels in the hyperproliferative epithelial cells of HGPIN and prostate cancer. BTG2 mRNA was detected in non-malignant prostate epithelial (PE) cells and in LNCaP cells, but not in PC-3 cells, consistent with p53-dependent regulation. In PE cells BTG2 protein was detected in areas of cell confluence by immunohistochemistry. BTG2 protein in LNCaP cells was undetectable by immunohistochemistry but was detected by immunoblotting at 8- to 9-fold lower levels than in PE cells. BTG2 protein levels were shown to be regulated by the ubiquitin-proteosome system. Forced expression of BTG2 in PC-3 cells was accompanied by a decreased rate of cell proliferation and decreased tumorigenicity of these cells in vivo. Taken together, these findings suggest that BTG2 functions as a tumor suppressor in prostate cells that is activated by cell quiescence, cell growth stimuli as part of a positive feedback mechanism and in response to DNA damage or other cell stress. The low steady-state levels of BTG2 protein in HGPIN and prostate cancer, a potential consequence of increased proteosomal degradation, may have important implications in the initiation and progression of malignant prostate lesions. Furthermore, these findings suggest that a significant component of the p53 G(1) arrest pathway might be inactivated in prostate cancer even in the absence of genetic mutations in p53.
Carcinogenesis 2001 Aug
PMID:Antiproliferative B cell translocation gene 2 protein is down-regulated post-transcriptionally as an early event in prostate carcinogenesis. 1147 Jul 58

The ubiquitin (Ub)-proteasome proteolytic system is highly selective, and the specific proteins involved in cell division, growth, activation, signaling and transcription are degraded at different rate depending on the physio-pathological state of the cell. Ubiquitination serves first of all as a signal for protein degradation of short-lived and abnormal proteins under several stressful conditions. The immunocytochemical localization of Ub in some malignant tumours has recently been presented and differences in Ub expression has been observed during malignant transformation. Change in the level of Ub and Ub-conjugated proteins might reflect a higher metabolic-catabolic ratio in neoplastic cells. Most studies have been focused on the malignant stage of tumour progression, and only a few papers have dealt with the change in Ub and Ub-protein conjugates level during the whole progression. To address this problem, we applied an azaserine-induced pancreatic carcinogenesis model, in which premalignant and malignant stages were investigated throughout the progression. The level of Ub immunoreactivity was measured in nucleus and cytoplasm by electron microscopic immunocytochemical and morphometrical methods. We found a significant increase of Ub level in the nucleus and the cytoplasmic area in premalignant atypical acinar cell nodule (AACN) cells and in malignant adenocarcinoma in situ (CIS) cells at month 20 after initiation.
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PMID:Ubiquitin cytochemical changes during azaserine-initiated pancreatic carcinogenesis. 1169 88

The ubiquitin system regulates diverse biological processes such as DNA replication and repair, biogenesis of ribosome, peroxisome and nucleosome, cell cycle, stress response and signal transduction pathways. Thus, the reported role of the ubiquitin system in apoptotic death control as well the alteration of its control in carcinogenesis should come as no surprise. Indeed, we and other groups have reported that the ubiquitin system is involved in apoptotic cell death of normal human lymphocytes and that this control is altered in B lymphocytes derived from chronic lymphocytic leukemia patients (B-CLL), rendering these malignant cells hypersensitive to specific inhibition of protein degradation/processing through proteasomal function. This approach recently allowed us to demonstrate that the stability of the tumor suppressor and pro-apoptotic protein p53 is differentially regulated in B-CLL versus normal lymphocytes and that this difference might at least partly explain the impaired response of B-CLL lymphocytes to apoptotic death activation. These results strongly suggest an imbalance in p53 regulation in B-CLL cells that leads to a variable response to DNA damage and constitutively expressed chromosomal instability. The question we and others would like to address is whether this alteration, or more likely a subset of alterations of the ubiquitin-proteasome pathway, is specific to B-CLL malignancy or if it is a hallmark of cancer cells in general. In either case, a better understanding of the ubiquitin-dependent control of apoptosis should pave the way towards a methodological approach for in vitro development of discriminating treatments which may be of potential usefulness in clinical trials of B-CLL.
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PMID:Chromosomal DNA and p53 stability, ubiquitin system and apoptosis in B-CLL lymphocytes. 1191 98

The Wnt signalling cascade plays an important role during embryonic patterning and cell fate determination and is highly conserved throughout evolution. Factors of the TCF/LEF HMG domain family (Tcfs) are the downstream effectors of this signal transduction pathway. Upon Wnt signalling, a cascade is initiated that results in the translocation of beta-catenin to the nucleus, where it interacts with Tcf to generate a transcriptionally active complex. This bipartite transcription factor is targeted to the upstream regulatory regions of Tcf target genes. In the absence of Wnt signals, beta-catenin is degraded in the cytoplasm via the ubiquitin-proteasome pathway. Several proteins are instrumental in achieving this tight regulation of beta-catenin levels in the cell, including adenomatous polyposis coli (APC), GSK3 beta, and Axin/Conductin. Deregulation of the Wnt signalling pathway is implicated in several forms of cancer, such as colon carcinoma and melanoma. This deregulation is achieved via mutation of APC, beta-catenin or Axin, resulting in elevated beta-catenin levels and the presence of constitutively active Tcf-beta-catenin complexes in the nucleus. The accompanying inappropriate activation of target genes is considered to be a critical, early event in this carcinogenesis. In addition to regulating beta-catenin levels, normal healthy cells have evolved a second level of regulation, by manipulating the activity of the Tcf proteins themselves. In the absence of Wnt signalling, Tcf complexes with several transcriptional repressor proteins ensuring active repression of Tcf target genes. In this review the dual role of Tcf proteins in the Wnt signalling cascade will be discussed.
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PMID:TCF: Lady Justice casting the final verdict on the outcome of Wnt signalling. 1193 63

The importance of protein degradation for controlling individual protein levels is long beyond doubt. Yet only recent experimental evidence confirmed the key role of the ubiquitin-proteasome degradation pathway in the cell cycle, carcinogenesis, transcription, cell differentiation, tissue growth and atrophy, metabolism of various substrates, selective elimination of abnormal proteins, and antigen processing. The review considers the structures of the 26S proteasome and its 20S proteolytic core, the system of ubiquitination of proteins bearing a degradation signal, the role of the 26S proteasome in various metabolic processes, and possible mechanisms regulating the proteasomal activity in the cell.
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PMID:[The proteasome: destroy to live]. 1239 38

Enzyme inducers such as 3H-1,2-dithiole-3-thione (D3T) enhance the detoxication of environmental carcinogens and protect against neoplasia. The putative molecular sensor for inducers is Keap1, a sulfhydryl-rich protein that sequesters the transcription factor Nrf2 in the cytoplasm. Expression of these detoxication enzymes is blunted in nrf2-deficient mice; moreover, these mice are more sensitive to carcinogenesis, and the protective actions of dithiolethiones are lost with nrf2 disruption. Hepatic gene expression profiles were examined by oligonucleotide microarray analysis in vehicle- or D3T-treated wild-type mice as well as in nrf2 single and keap1-nrf2 double knockout mice to identify those genes regulated by the Keap1-Nrf2 pathway. Transcript levels of 292 genes were elevated in wild-type mice 24 h after treatment with D3T; 79% of these genes were induced in wild-type, but not nrf2-deficient mice. These nrf2-dependent, D3T-inducible genes included known detoxication and antioxidative enzymes. Unexpected clusters included genes for chaperones, protein trafficking, ubiquitin/26 S proteasome subunits, and signaling molecules. Gene expression patterns in keap1-nrf2 double knockout mice were similar to those in nrf2-single knockout mice. D3T also led to nrf2-dependent repression of 31 genes at 24 h; principally genes related to cholesterol/lipid biosynthesis. Collectively, D3T increases the expression of genes through the Keap1-Nrf2 signaling pathway that directly detoxify toxins and generate essential cofactors such as glutathione and reducing equivalents. Induction of nrf2-dependent genes involved in the recognition and repair/removal of damaged proteins expands the role of this pathway beyond primary control of electrophilic and oxidative stresses into secondary protective actions that enhance cell survival.
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PMID:Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. 1250 15

Certain types of human papillomaviruses have been etiologically associated with malignant lesions, most notably with cervical cancer. The major oncoproteins of these cancer-associated viruses are encoded by the viral E6 and E7 genes. Thorough characterization of these oncoproteins and their interaction with cellular proteins has shown that both E6 and E7 exploit the ubiquitin-proteasome system to degrade and, thus, to functionally inactivate negative cell-regulatory proteins including members of the p110(RB) family and p53. This act of piracy is assumed to contribute to both the efficient propagation of HPVs and HPV-induced carcinogenesis.
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PMID:Human papillomavirus-induced carcinogenesis and the ubiquitin-proteasome system. 1250 57

Invasive cervical cancer remains a leading cause of morbidity and mortality, especially among women in the developing world where screening is either deficient or absent. Of all agents linked to the causation of this disease, high-risk human papillomavirus (HPV) appears to be the strongest factor. However, not all women with HPV develop cervical cancer. Steroid contraception has been postulated to be one mechanism whereby HPV exerts its tumorigenic effect on cervical tissue. Steroids are thought to bind to specific DNA sequences within transcriptional regulatory regions on the HPV DNA to either increase or suppress transcription of various genes. Although some earlier studies were reassuring as no increased incidence of cervical cancer was observed, subsequent research has shown a causative association, especially among long-term users. The role of steroids was further enhanced by the discovery of hormone receptors in cervical tissue. Some earlier studies of oral contraceptive steroids found no increased risk, even after controlling for other risk factors, including smoking and number of partners. However, prospective studies have shown a greater progression of dysplasia to carcinoma-in-situ with more than 6 years of oral steroid contraceptive use. Similar findings were also evident from other work, including the Royal College of General Practitioners Oral Contraception Study. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives showed a relative risk of 1.2 for invasive cancer in users of the long-acting progestational contraceptive, depo-medroxyprogesterone acetate. However, in users of more than 5 years duration, an estimate of 2.4 was reported. The upstream regulatory region (URR) of the HPV type 16 viral genome, mediates transcriptional control of the HPV genome and is thought to contain enhancer elements that are activated by steroid hormones. It has been shown that steroid hormones bind to specific glucorticoid-response elements within HPV-DNA. Experimental evidence has revealed that high-risk type HPV 16 are able to stimulate the development of vaginal and cervical squamous cell carcinomas in transgenic mice exposed to slow-release pellets of 17 beta-estradiol in the presence of human keratin-14 promoter. Squamous cell carcinomas developed in a multi-stage pathway only in transgenic mice and not in nontransgenic mice. The E6 oncoprotein of HPV 16 has been shown to bind to the p53 tumor suppressor gene and stimulate its degradation by a ubiquitin-dependent protease system. Steroid hormones are thought to increase the expression of the E6 and E7 HPV 16 oncogenes, which in turn bind to and degrade the p53 gene product, leading to apoptotic failure and carcinogenesis. However, the molecular basis of this remains to be proven.
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PMID:The role of steroid contraceptive hormones in the pathogenesis of invasive cervical cancer: a review. 1265 8

Human papillomavirus (HPV) E6 viral oncoprotein plays an important role during cervical carcinogenesis. This oncoprotein binds the tumor suppressor protein p53, leading to its degradation via the ubiquitin-proteasome pathway. Therefore, it is generally assumed that in HPV-positive cancer cells p53 function is completely abolished. Nevertheless, recent findings suggest that p53 activity can be recovered in cells expressing endogenous E6 protein. To investigate whether p53-dependent functions controlling genome integrity, cell proliferation, and apoptosis can be reactivated in cervical cancer cells, we examined the capacity of HeLa, INBL, CaSki, C33A, and ViBo cell lines to respond to neocarzinostatin (NCS), a natural product which induces single- and double-strand breaks in DNA. We found that NCS treatment inhibits cellular proliferation through G2 cell cycle arrest and apoptosis induction. This effect was preceded by nuclear accumulation of p53 protein and by an increase of p21 transcripts. Although apoptosis was blocked in ViBo cells (HPV-negative), nuclear accumulation of transcriptionally active p53 and inhibition of cell proliferation are observed after NCS treatment. These results suggest that HPV-positive cervical cancer cells are capable of responding efficiently to DNA damage provoked by NCS treatment through a p53-dependent pathway in spite of the presence of E6 protein.
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PMID:Neocarzinostatin induces an effective p53-dependent response in human papillomavirus-positive cervical cancer cells. 1275 Apr 35

Reversible down-regulation of gap junctional intercellular communication (GJIC) is proposed to be an important cellular mechanism in tumor promotion. Gap junction function is modified by a variety of tumor promoters, including the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Treatment of cells with TPA results in the activation and subsequent depletion of the TPA-responsive protein kinase C (PKC) isoforms. TPA-induced degradation of the PKC isoforms alpha, delta and epsilon was recently shown to occur via the ubiquitin-proteasome pathway. In the present study we investigated the role of the proteasome in the TPA-induced modification of GJIC in IAR20 rat liver epithelial cells. TPA exposure of IAR20 cells induced hyperphosphorylation of gap junction protein connexin43 and inhibition of GJIC. Prolonged TPA treatment induced down-regulation of PKCalpha, delta and epsilon and a reduction in the total PKC activity, which was associated with recovery of GJIC. Co-treatment of IAR20 cells with TPA and the proteasomal inhibitor MG132 suppressed down-regulation of PKCalpha, delta and epsilon and caused prolonged PKC activity. Under these conditions, the recovery of GJIC was blocked. The general PKC inhibitor GF109203X reversed the effect of MG132, indicating that the prolonged TPA-induced inhibition of GJIC caused by MG132 was due to the prolonged PKC activity. These results indicate that proteasomal degradation of PKC is one mechanism by which the recovery of GJIC after TPA treatment is regulated.
Carcinogenesis 2003 Jul
PMID:Recovery of gap junctional intercellular communication after phorbol ester treatment requires proteasomal degradation of protein kinase C. 1280 62


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