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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the possible role of insulin-like growth factor-I (IGF-I) and IGF-I receptor (IGF-Ir) during multistage carcinogenesis in mouse skin. For this purpose, the expression of both IGF-I and IGF-Ir was investigated in mouse skin during tumor promoter treatment and in primary papillomas and squamous cell carcinomas (SCCs) obtained from SENCAR mice treated with standard initiation-promotion regimens. IGF-I transcripts were not detectable or only weakly detectable in normal SENCAR mouse epidermis by northern or reverse transcription (RT)-polymerase chain reaction (PCR) analysis, respectively, whereas IGF-I transcripts (primarily a 7.0-kb transcript) were readily detected in RNA preparations from the dermis by both northern blot analysis and RT-PCR analysis. In contrast, IGF-Ir transcripts were observed in RNA samples from both epidermis and dermis of control SENCAR mice. Single and multiple topical treatments with 3.4 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA) had no effect on dermal or epidermal IGF-I and IGF-Ir mRNA levels. In contrast, the levels of IGF-I transcripts were elevated (2.5- to 15-fold) in a significant number of mouse skin tumors (71% of all tumors examined). Transcripts of 7.0, 2.5, and 1.3 kb were more consistently overexpressed in skin tumors compared with epidermis, whereas the two smaller transcripts were most consistently overexpressed compared with the dermis. The levels of an 11.0-kb IGF-Ir transcript were also elevated (2.5- to 8-fold) in some papillomas (20%) and SCCs (55%), but the percentage of tumors exhibiting this property (32% of all tumors examined) was lower than the percentage overexpressing IGF-I. These data suggest that altered expression of IGF-I and IGF-Ir may play a role in multistage carcinogenesis in the mouse skin model. The inability of TPA to induce elevated IGF-I or IGF-Ir expression suggests that these changes in skin tumors are coincident with tumor formation and not a direct result of altered epidermal proliferation per se. Altered expression of IGF-I in a high percentage of papillomas may indicate that IGF-I has an important role in the development of autonomous growth in these tumors. The higher percentage of SCCs with altered levels of IGF-Ir mRNA may indicate a role for these changes in the later stages (i.e., tumor progression) of carcinogenesis in this model system.
Mol Carcinog 1996 Oct
PMID:Altered expression of insulin-like growth factor I and its receptor during multistage carcinogenesis in mouse skin. 889 Sep 54

The protein kinase C (PKC) signal transduction pathway is the prototype of a growth factor-responsive intracellular signaling system, which is activated by various cytokines, growth factors and tumor promoters, such as the phorbol ester 12-O-tetradecanoyl-phorbol acetate (TPA). To date, a large number of different PKC isoforms has been identified, the physiological relevance of which is unknown. Moreover, the expression pattern of PKC isoforms in uterine cells has not been studied as yet. To study the functional role of differential PKC isoform expression in uterine tumor progression, we have compared the proliferative response to TPA, changes in cell morphology induced by TPA, and the PKC isoform expression pattern in two uterine tumor cell lines of different origin. The moderately differentiated endometrial HEC-1-B adenocarcinoma cell line showed a marked increase in proliferative activity and a profound morphological change in response to TPA. In contrast, TPA did not induce cell proliferation and/or morphological changes in the well-differentiated SKUT-1-B mixed mesodermal cell line. Analysis of the PKC isoform expression profile by Western blot revealed that PKC alpha, betaI, delta, epsilon, and zeta were expressed at a much higher level in HEC-1-B as compared to SKUT-1-B cells. PKC beta11 was the only isoenzyme to exhibit a higher expression level in SKUT-1-B cells. This is the first study analyzing the PKC isoform expression profile in uterine tumor cells. Our data demonstrate that the proliferative response to TPA correlates with the expression levels of the majority of PKC isoforms in these cells. Overexpression of PKC isoforms indicates a higher proliferative capacity, and may, thus, represent an important step in the pathogenesis of certain uterine malignancies.
Mol Cell Endocrinol 1996 Oct 14
PMID:Protein kinase C (PKC) isoenzyme expression pattern as an indicator of proliferative activity in uterine tumor cells. 891 14

Recent studies have implicated a role for midkine (MK) in cancer progression. This is based upon its structural homology with pleiotrophin, an angiogenic growth factor, and its ability to enhance fibrinolytic activity of bovine endothelial cells. To investigate whether MK plays a role in breast cancer, we examined MK mRNA expression in N-nitroso-N-methylurea-induced rat mammary tumors at various stages of tumor progression, including hormone independence and distant metastasis. Well-differentiated mammary adenocarcinomas showed levels of MK comparable to those of normal mammary gland. A 10- to 20-fold reduction in MK mRNA levels was observed in mammary tumors that had progressed to hormone independence and metastasis. The data suggest that loss of MK expression correlates with breast tumor progression. Treatment of rat mammary tumor cell lines with retinoic acid increased MK expression, decreased proliferation, and markedly reduced colony-forming efficiency in agar. This raises the possibility that agents that upregulate MK could have potential in prevention and therapy by causing breast cells to terminally differentiate.
Mol Carcinog 1996 Nov
PMID:Midkine in the progression of rat N-nitroso-N-methylurea-induced mammary tumors. 894 70

Loss of heterozygosity (LOH) is one of the most common genetic abnormalities in cancer. To define the role of LOH and chromosomal abnormalities at various stages of mouse mammary cancer progression, we analyzed the allelotypes and karyotypes of primary mammary tumors induced in CD2F, mice by two basic protocols, the classical multiple-dose 7,12-dimethylbenz[a]anthracene (DMBA) protocol and a novel protocol of combined medroxyprogesterone acetate (MPA) and DMBA. The advantage of the latter protocol is that its latency for tumor development is much shorter and its tumor incidence is higher than those of DMBA alone. To study more advanced stages of mammary tumor progression, we also analyzed mouse mammary tumors that had acquired autonomous growth and were transplantable into syngeneic hosts. The allelotypic studies were performed by means of microsatellite length polymorphism analysis with a minimum of two simple-sequence repeat markers per chromosome. We observed that MPA-DMBA-induced mammary adenocarcinomas, which in general arose earlier because of the growth promotion exerted by MPA, did not show any significant LOH and were essentially diploid. Tumors induced by DMBA alone, which on average took longer to develop, showed a higher frequency of allelic losses. LOH on chromosome 11 was observed in 30% of the cases. Chromosomes 4 and 8 were affected in 25% and 20% of the tumors, respectively. Interestingly, advanced stages of mammary tumor progression, represented by transplantable mammary tumors, showed a much higher level of genomic instability, specifically a very high frequency (66%) of LOH on chromosome 4. These findings indicate that chromosome 4 harbors a gene whose inactivation may play a role in the acquisition of more aggressive characteristics such as autonomous growth and transplantation ability.
Mol Carcinog 1996 Nov
PMID:Allelotypic and cytogenetic characterization of chemically induced mouse mammary tumors: high frequency of chromosome 4 loss of heterozygosity at advanced stages of progression. 894 72

Prostate epithelial differentiation is dictated by its surrounding stroma which determines androgen induced growth responsiveness and expression of specific secretory proteins in normal prostate gland. During neoplastic progression, organ specific stroma has been shown to determine the rate of neoplastic progression from androgen-dependent to androgen-independent and metastatic states. Although growth factors and extracellular matrix are recognized as important contributors to prostate epithelial growth, hormonal responsiveness, and neoplastic progression, the exact mechanism of intercellular communication between stromal and epithelial cells remains undefined. In addition to the importance of defining the reciprocal interaction between stromal and epithelial interaction in the prostate, clonal interaction between two dissimilar prostate epithelial cell is also recognized to contribute to disease progression. In this review, we summarized recent advances made in delineating molecular mechanisms underlying stromal epithelial interaction and clonal interaction between androgen-dependent and androgen-independent prostate cancer cells in vivo and in culture. Understanding cellular interaction between prostate epithelium and its surrounding stroma could help us in developing metastatic models of prostate carcinogenesis. This concept will allow us to define epithelial-specific markers, markers induced as the result of stromal-epithelial interaction, and stroma-associated markers. These markers together will assist us in diagnosing, preventing, prognosing and treating prostate cancer more efficaciously in the future.
Mol Biol Rep 1996
PMID:Prostate epithelial differentiation is dictated by its surrounding stroma. 898 15

The bic locus is a common retroviral integration site in avian leukosis virus (ALV)-induced B-cell lymphomas originally identified by infection of chickens with ALVs of two different subgroups (Clurman and Hayward, Mol. Cell. Biol. 9:2657-2664, 1989). Based on its frequent association with c-myc activation and its preferential activation in metastatic tumors, the bic locus is thought to harbor a gene that can collaborate with c-myc in lymphomagenesis and presumably plays a role in late stages of tumor progression. In the present study, we have cloned and characterized two novel genes, bdw and bic, at the bic locus. bdw encoded a putative novel protein of 345 amino acids. However, its expression did not appear to be altered in tumor tissues, suggesting that it is not involved in oncogenesis. The bic gene consisted of two exons and was expressed as two spliced and alternatively polyadenylated transcripts at low levels in lymphoid/hematopoietic tissues. In tumors harboring bic integrations, proviruses drove bic gene expression by promoter insertion, resulting in high levels of expression of a chimeric RNA containing bic exon 2. Interestingly, bic lacked an extensive open reading frame, implying that it may function through its RNA. Computer analysis of RNA from small exon 2 of bic predicted extensive double-stranded structures, including a highly ordered RNA duplex between nucleotides 316 and 461. The possible role of bic in cell growth and differentiation is discussed in view of the emerging evidence that untranslated RNAs play a role in growth control.
Mol Cell Biol 1997 Mar
PMID:bic, a novel gene activated by proviral insertions in avian leukosis virus-induced lymphomas, is likely to function through its noncoding RNA. 903 77

Loss of wild-type p53, either through deletion or mutation, has been demonstrated in most squamous cell carcinomas of the head and neck (HNSCC). Whether these mutant molecules contribute to tumor progression purely through loss of wild-type functions or by growth-promoting mechanisms, however, remains unclear. To begin to address these issues, we isolated a series of p53 cDNAs from HNSCC cell lines that contain missense or nonsense point mutations, insertions, or deletions. The ability of each of these molecules to transform NIH/3T3 cells to a malignant phenotype was assessed by stable transfection and expression under the control of a strong heterologous promoter. NIH/3T3 cells transfected with pLTR6p53, which harbors an H179L missense mutation, formed large tumors rapidly (in less than 4 wk) when transplanted to athymic mice, as did cells expressing pLTR13p53, which had undergone a V173F missense mutation and an in-frame deletion of 48 bp between codons 208 and 223. Cells transfected with pLTR17p53, predicted from the nucleotide sequence to encode a severely truncated p53 corresponding to the N-terminal 56 amino acids, also formed tumors. Cells transfected with pLTR15p53, which was predicted to encode a less severely truncated molecule, formed much smaller tumors and at lower frequencies. NIH/3T3 cells transfected with pLTR12p53 (exon 7 splice donor mutant), pLTRwtp53 (wild-type p53), or vector alone failed to form tumors for up to 2 mo after transplantation. pLTR6p53-transfected cells exhibited a highly malignant phenotype with invasion of regional lymph nodes, mediastinal and lung metastases, invasion of the abdominal wall, and dissemination throughout the peritoneal cavity. Histological assessment of the tumors revealed intensely vascularized fibrosarcomas with numerous cellular atypia, including frequent and aberrant mitoses. Tumor explants were recultured, and northern blot analysis of cellular RNA confirmed that the expression of exogenous p53 was maintained in each case. These data indicate that different p53 mutants contribute to tumorigenesis by specific mechanisms. Furthermore, the results obtained by using the pLTR17p53 transfectants imply that some truncated molecules may overcome the effects of wild-type p53 to contribute to malignancy.
Mol Carcinog 1997 Feb
PMID:Functional characterization in vivo of mutant p53 molecules derived from squamous cell carcinomas of the head and neck. 904 83

Nuclear receptors for retinoic acid are important modulators of epidermal cell proliferation and terminal differentiation. Aberrant expression of retinoic acid receptors (RARs) and retinoid X receptors in the epidermis has been associated with altered differentiation capacity and tumor progression. In this study, we describe a human squamous cell carcinoma line, SCC 12F, which displays reduced RARgamma expression and diminished responsiveness to retinoic acid. When compared with normal keratinocytes or other squamous cell carcinoma lines that display normal levels of RARgamma, several measures of cellular response to retinoic acid are altered in SCC 12F cells, including inhibition of cornified envelope formation, reduction of involucrin mRNA expression, and transcriptional regulation of the involucrin gene. Normal patterns of ligand-dependent transcriptional response were restored upon co-transfection of an expression vector containing either RARalpha or RARgamma. Our findings demonstrate that reduced expression of RAR may have direct functional consequences with regard to keratinocyte differentiation and that the defect may be alleviated by reintroduction of functional receptor.
Mol Pharmacol 1997 Mar
PMID:Functional consequences of reduced retinoic acid receptor gamma expression in a human squamous cell carcinoma line. 905 91

An androgen receptor (AR) gene mutation identified in the androgen-dependent human prostate cancer xenograft, CWR22, changed codon 874 in the ligand-binding domain (exon H) from CAT for histidine to TAT for tyrosine and abolished a restriction site for the endonuclease SfaNI. SfaNI digestion of AR exon H DNA from normal but not from prostate cancer tissue indicated H874Y is a somatic mutation that occurred before the initial tumor transplant. CWR22, an epithelial cell tumor, expresses a 9.6-kb AR mRNA similar in size to the AR mRNA in human benign prostatic hyperplasia. AR protein is present in cell nuclei by immunostaining as in other androgen-responsive tissues. Transcriptional activity of recombinant H874Y transiently expressed in CV1 cells in the presence of testosterone or dihydrotestosterone was similar to that of wild type AR. With dihydrotestosterone at a near physiological concentration (0.01 nM), H874Y and wild type AR induced 2-fold greater luciferase activity than did the LNCaP mutant AR T877A. The adrenal androgen, dehydroepiandrosterone (10 and 100 nM) with H874Y stimulated a 3- to 8-fold greater response than with wild type AR and at 100 nM the response was similar with the LNCaP mutant. H874Y, like the LNCaP cell mutant, was more responsive to estradiol and progesterone than was wild type AR. The antiandrogen hydroxyflutamide (10 nM) had greater agonist activity (4- to 7-fold) with both mutant ARs than with wild type AR. AR mutations that alter ligand specificity may influence tumor progression subsequent to androgen withdrawal by making the AR more responsive to adrenal androgens or antiandrogens.
Mol Endocrinol 1997 Apr
PMID:Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. 909 97

Cyclins and cyclin-dependent kinases (Cdks) are central to regulation of the cell cycle. Their abnormal expression may cause loss of cell-cycle control and result in autonomous cell growth, a critical feature of neoplasias. In this study, using immunoblotting, we analyzed the protein levels of several G1/S cyclins (cyclins D1, D2, D3, A, and E) and their respective Cdks (Cdk 2, 4, and 6) in 17 mouse squamous cell carcinomas (SCCs) and 18 mouse skin tumor cell lines. Overexpression of these cell cycle-related genes was frequent in tumors and cell lines. Of special interest was the fact that a group of cell lines that became more aggressive after animal passaging expressed more cyclins D2 and D3 than their respective parental lines did. In addition, SCCs had higher cyclin D3 expression levels than papillomas, and metastases had higher levels than the respective primary tumors, indicating that overexpression of cyclin D3 may be associated with increased aggressiveness of mouse SCC. Interestingly, overexpression of cyclin E was seen in most SCCs induced by a complete carcinogenesis protocol with benzo[a]pyrene (B(a)P) and only in a few SCCs induced by a two-stage carcinogenesis protocol using 7,12-dimethylbenz[a]anthracene as initiator. In contrast, more of the latter tumors overexpressed cyclin D1 and D2 than those induced by B(a)P. Thus, it is possible that different components of the cell-cycle machinery are involved in proliferative dysfunctions that take place during tumor development with different carcinogenesis protocols. Taken together, these results indicate that overexpression of G1 cyclins and their related Cdks is a significant molecular abnormality that could be involved in the process of tumor progression.
Mol Carcinog 1997 Mar
PMID:Increased expression of G1 cyclins and cyclin-dependent kinases during tumor progression of chemically induced mouse skin neoplasms. 911 84


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