Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Normal cells have a strictly limited growth potential and senesce after a defined number of population doublings (PDs). In contrast, tumor cells often exhibit an apparently unlimited proliferative potential and are termed immortalized. Although spontaneous immortalization of normal human cells in vitro is an extremely rare event, we observed this in fibroblasts from an affected member of a Li-Fraumeni syndrome kindred. The fibroblasts were heterozygous for a p53 mutation and underwent senescence as expected at PD 40. In four separate senescent cultures (A to D), there were cells that eventually recommenced proliferation. This was associated with aneuploidy in all four cultures and either loss (cultures A, C, and D) or mutation (culture B) of the wild-type (wt) p53 allele. Loss of wt p53 function was insufficient for immortalization, since cultures A, B, and D subsequently entered crisis from which they did not escape. Culture C has continued proliferating beyond 400 PDs and thus appears to be immortalized. In contrast to the other cultures, the immortalized cells have no detectable p16INK4 protein. A culture that had a limited extension of proliferative potential exhibited a progressive decrease in telomere length with increasing PD. In the culture that subsequently became immortalized, the same trend occurred until PD 73, after which there was a significant increase in the amount of telomeric DNA, despite the absence of telomerase activity. Immortalization of these cells thus appears to be associated with loss of wt p53 and p16INK4 expression and a novel mechanism for the elongation of telomeres.
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PMID:Alterations in p53 and p16INK4 expression and telomere length during spontaneous immortalization of Li-Fraumeni syndrome fibroblasts. 765 92

The CDKN2 gene located on chromosome 9p21 encodes the cyclin-dependent kinase-4 inhibitor p16. This gene is a putative tumor-suppressor gene because of its frequent alterations in many kinds of tumor cell lines. We analyzed the CDKN2 gene to evaluate its alterations in 52 primary specimens of non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) of B-cell origin by Southern blot analysis, polymerase chain reaction-mediated single-strand conformation polymorphism (PCR-SSCP) analysis, and direct sequencing. By Southern blot analysis, we showed homozygous deletion of the CDKN2 gene in 3 of 42 patients with B-NHL (7.1%). After screening by PCR-SSCP analysis, direct sequencing identified one missense mutation at codon 72 (nucleotide 233) and two frameshifts due to a 35-bp deletion arising at codon 49 (nucleotides 163 to 175) in patients with B-NHL (3 of 42, 7.1%). In the patient carrying the missense mutation, hemizygous deletion of the CDKN2 gene was also suspected. In this study, we detected alterations in CDKN2 in 6 of 42 patients (14.3%) with B-NHL and in none of 10 patients with B-CLL. Our results suggest that the CDKN2 alterations contribute in tumorigenesis in some patients with B-NHL.
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PMID:Mutational analysis of the CDKN2 (MTS1/p16ink4A) gene in primary B-cell lymphomas. 767 Jan 11

Tumor suppressor gene CDKN2 (also called MTS1, CDK4I and p16INK4) is located in 9p21 and deleted homozygously in a high percentage of tumor cell lines. We have examined the sequence of CDKN2 in 154 tumor cell lines that are not homozygously deleted for CDKN2. Overall, 18% (27/154) of the cell lines carried mutations in CDKN2. These mutations were found in cell lines derived from melanoma, bladder, lung and prostate cancers, as well as sarcomas of various origin. The spectrum of the CDKN2 mutations found in melanoma cell lines indicated a major role for ultraviolet light in generating the mutations, suggesting the mutations occurred in vivo. The frequency of loss of heterozygosity in 9p21 in this set of lines is only slightly higher than the background rate of aneuploidy, suggesting that a second 9p21 tumor suppressor gene, if it exists, must lie near CDKN2.
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PMID:CDKN2 (MTS1) tumor suppressor gene mutations in human tumor cell lines. 857 Jan 98

Recently the putative tumor suppressor gene p16INK4 was mapped to human chromosome 9p21, which is homologous to rat chromosome 5. Monosomy of rat chromosome 5 occurs with high frequency in rat kidney tumor-derived cell lines (ERC lines). Thus, we studied these lines in order to investigate the involvement of p15INK4B and p16INK4 in the genesis of this tumor type. p15INK4B and p16INK4 were found by Southern blot analysis to be codeleted in five of seven of these lines. This was confirmed by Northern blot analysis with a probe for the rat p15INK4B gene. In normal rat tissues, expression of p15INK4B was abundant in lung (2.5 and 2.0 kilobases), less abundant in testis (2.5, 2.0, 1.1, and 0.9 kilobases), barely detectable in liver (2.0 kilobases), and not detectable in neonatal kidney, adult kidney, brain, heart, or spleen. In the ERC lines, p15INK4B was expressed as a single 2.0-kilobase transcript observed only in those cell lines in which the gene was detected by Southern blot analysis. However, neither p15INK4B nor p16INK4 were deleted in 12 of 12 primary kidney tumors examined, suggesting that deletion of these genes is not directly involved in the process of renal tumor development but may be related to tumor progression or autonomous growth in vitro. A panel of rat kidney epithelial cell lines chemically transformed in vitro (TRKE lines) that had high-frequency monosomy 5 were also examined, but deletion of p15INK4B and p16INK4 was observed in only one of six of the TRKE lines. To our knowledge, this is the first reported investigation of these genes in rodent tumors and cell lines, and its data support the theory that alterations of genes located in the INF region of rat chromosome 5 may play a role in rodent cell transformation.
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PMID:Association of rat p15INK4B/p16INK4 deletions with monosomy 5 in kidney epithelial cell lines but not primary renal tumors. 771 60

The p16 gene, also referred to as MTS1, INK4, CDK4I, or CDKN2, at chromosome 9p21 has recently been described as a tumor suppressor that may be involved in a wide range of tumors. We have used a semiquantitative multiplex polymerase chain reaction assay to search for deletions of the p16 gene in 34 patients with chronic myeloid leukemia in blast crisis (CML BC), 19 patients with acute lymphoblastic leukemia (ALL), and 25 patients with acute myeloid leukemia (AML). Homozygous deletions of p16 exons were found in 5 of 10 (50%) patients with CML in lymphoid BC and in 5 (26%) ALL patients, but in only 1 (2%) case with AML. No deletions were found in CML BC of nonlymphoid phenotype. Comparison of chronic phase DNA or remission DNA with acute leukemia DNA in 5 individuals showed that the p16 deletions were acquired and not inherited, directly implicating these lesions in the pathogenesis of the disease. We conclude that functional elimination of the p16 gene, or a closely mapping gene, is involved in a significant number of patients with CML in lymphoid transformation.
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PMID:Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia. 771 73

To elucidate the regulator-versus-target relationship in the cyclin D1/cdk4/retinoblastoma protein (pRB) pathway, we examined fibroblasts from RB-1 gene-deficient and RB-1 wild-type littermate mouse embryos (ME) and in human tumor cell lines that differed in the status of the RB-1 gene. The RB+/+ and RB-/- ME fibroblasts expressed similar protein levels of D-type cyclins, cdk4, and cdk6, showed analogous spectra and abundance of cellular proteins complexed with cdk4 and/or cyclins D1 and D2, and exhibited comparable associated kinase activities. Of the two human cell lines established from the same sarcoma biopsy, the RB-positive SKUT1B cells contained cdk4 that was mainly associated with D-type cyclins, contrary to a predominant cdk4-p16INK4 complex in the RB-deficient SKUT1A cells. Antibody-mediated neutralization of cyclin D1 arrested the RB-positive ME and SKUT1B cells in G1, whereas this cyclin appeared dispensable in the RB-deficient ME and SKUT1A cells. Lack of requirement for cyclin D1 therefore correlated with absence of functional pRB, regardless of whether active cyclin D1/cdk4 holoenzyme was present in the cells under study. Consistent with a potential role of cyclin D/cdk4 in phosphorylation of pRB, monoclonal anti-cyclin D1 antibodies supporting the associated kinase activity failed to significantly affect proliferation of RB-positive cells, whereas the antibody DCS-6, unable to coprecipitate cdk4, efficiently inhibited G1 progression and prevented pRB phosphorylation in vivo. These data provide evidence for an upstream control function of cyclin D1/cdk4, and a downstream role for pRB, in the order of events regulating transition through late G1 phase of the mammalian cell division cycle.
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PMID:Cyclin D1 is dispensable for G1 control in retinoblastoma gene-deficient cells independently of cdk4 activity. 773 41

Adult T-cell leukemia (ATL) is associated with prior infection with human T-cell leukemia virus type I (HTLV-I). Twenty to 40 years often elapse from viral infection to overt ATL, suggesting that other genetic events must occur to produce frank leukemia. The p15 (MTS2) and p16 (CDKN2/MTS1) genes located on chromosome 9p have been implicated as candidate tumor-suppressor genes in several types of tumors. We examined for alterations of these genes in ATL using Southern blot and polymerase chain reaction-single-strand conformation polymorphism analyses. Both p15 and p16 genes were homozygously deleted in 4 of 23 acute/lymphomatous ATL (17%). An additional 3 (13%) and 4 (17%) acute/lymphomatous samples had hemizygous deletions in at least one exon of p15 and p16, respectively. One of 14 chronic ATL samples had a homozygously deleted p16 gene and another had a hemizygous deletion of p16. Neither homozygous nor hemizygous deletions of the p15 gene were found in chronic ATL. In total, 10 of 37 (27%) ATL samples had loss of the p15 and/or p16 genes. No point mutations of the p15 and p16 genes were found. The ATL patient with a homozygously deleted p16 in the chronic phase rapidly progressed to acute ATL and died within 6 months of the initial diagnosis. One instructive patient had no detectable deletion of the p15 and p16 genes during the chronic phase of ATL but had a homozygous deletions of both genes when she progressed to acute ATL. Our results suggest an association of p15/p16 deletions with development of acute ATL.
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PMID:Homozygous deletions of the p15 (MTS2) and p16 (CDKN2/MTS1) genes in adult T-cell leukemia. 774 29

Mutations of CDKN2 have been found recently in melanoma and many other tumor types. Neuroblastoma shares with melanoma a neuroectodermal origin and a high incidence of deletions of the short arm of chromosome 1. Therefore, we analyzed 18 primary neuroblastomas and 9 tumor-derived cell lines for mutations in CDKN2. We used PCR-single-strand conformation polymorphism to examine exons 1 and 2 of the CDKN2 gene for mutations, but none were detected. Furthermore, no homozygous deletions were detected and there was no loss of heterozygosity at the closely linked IFNA locus. We conclude that disruption of the CDKN2 gene is not required for malignant transformation of human neuroblastomas.
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PMID:No CDKN2 mutations in neuroblastomas. 774 1

We have examined 41 forms of ovarian cancer for genetic alterations on chromosome 9 using a combination of five RFLP DNA probes and 15 simple tandem repeat polymorphisms. Genetic imbalance (i.e., loss of heterozygosity, microsatellite instability, amplification) for 1 or more informative markers on chromosome 9 was observed in 66% (27 of 41) of our tumor panel. Genetic imbalance was observed on 9q in 59% (24 of 41) of tumors informative for at least one locus. In contrast, only 13% (5 of 40) of informative tumors demonstrated a genetic alteration involving 9p. Furthermore, allelic loss on 9q was more common in late stage tumors (63%, 17 of 27) and poorly differentiated tumors (75%, 15 of 20) as compared to benign and early stage tumors (30%, 3 of 10). Evaluation of 15 tumors showing limited regions of genetic imbalance has identified 2 candidate tumor suppressor regions on 9q and 1 on 9p. Interestingly, the regions defined to 9p21-p24, 9q31, and 9q32-q34 all overlap with several known disease loci. In this aspect, the potential role of the CDKN2 gene at 9p21-p22 in ovarian carcinogenesis was assessed in an extended panel of ovarian tumors, 11 human ovarian carcinoma cell lines, and 1 cervical tumor cell line. With the use of comparative multiplex PCR, homozygous deletions were detected in 16 of 115 (14%) fresh tumors and 3 of 12 cancer cell lines. For those tumors demonstrating allelic loss for markers on 9p no somatic mutations were observed in the retained allele of CDKN2, as determined by single-strand conformation polymorphism analysis, but a mutation was observed in an additional cell line. Furthermore, CDKN2 mRNA levels were similar in the 9 cancer cell lines that retain CDKN2, as compared to normal human ovarian surface epithelial cell lines. Overall, our results suggest the potential involvement of a gene or genes on chromosome 9q and de-emphasize a significant role for the CDKN2 gene on 9p in the initiation and progression of ovarian cancer.
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PMID:Characterization of chromosome 9 in human ovarian neoplasia identifies frequent genetic imbalance on 9q and rare alterations involving 9p, including CDKN2. 774 16

The 9p21 region of human chromosome 9 is a hot spot for chromosomal aberrations in both cultured cell lines and primary tumors. This region contains a gene, P16 (also called MTS1, CDKN2 and p16INK4), that encodes a presumptive negative cell cycle regulator called p16. P16 is deleted or mutated at high frequency in a variety of tumor cell lines including melanoma and bladder carcinoma lines. As such, it is likely to be a tumor suppressor gene. Here we show that P16 is mutated in primary bladder carcinomas (3 of 33) and melanomas (5 of 34). These findings support studies that show P16 mutations are not solely a product of growth in tissue culture but rather are involved in formation of tumors in viva. Some bladder primary tumors and some bladder and melanoma tumor cell lines contain mutations in both P16 and P53 at frequencies that suggest that p53 and p16 function in different pathways, each of which is important in suppressing malignant transformation.
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PMID:Genetic evidence in melanoma and bladder cancers that p16 and p53 function in separate pathways of tumor suppression. 774 14


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