Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.01 seconds)

Tyrosine phosphorylation status was investigated during mouse mammary tumor development using non-tumorigenic and tumorigenic hyperplastic outgrowth lines. These outgrowth lines were compared with normal mammary glands from pregnant mice and with their corresponding tumors. The levels of total tyrosine phosphorylation in proteins of hyperplastic and neoplastic tissues were 4.7- and 3.4-fold higher than in the normal gland respectively. These results indicate that increases in tyrosine phosphorylation occur in the earliest stages of neoplastic development and are not restricted to neoplastic cells per se. These results led to the identification of the specific proteins showing high levels of tyrosine phosphorylation. Of the eight molecular weight bands of proteins exhibiting detectable levels of tyrosine phosphorylation, the only proteins exhibiting consistently different degrees of phosphorylation between hyperplasias and tumors were of approximately 34 kDa. In a series of six different hyperplasias with tumorigenic potentials ranging from 0 to 93%, the extent of tyrosine phosphorylation of 34 kDa proteins correlated inversely with tumorigenic potential. The levels of p34cdc2 and p33cdk2 proteins were examined, using antibodies specific for the cdc2 and cdk2 proteins. The amounts of p34cdc2 and p33cdk2 proteins were low in non-tumorigenic (TM3 and TM2L) compared to tumorigenic hyperplasias and correlated inversely with tyrosine phosphorylation of 34 kDa proteins during tumor development. Thus in the non-tumorigenic hyperplasias (TM2L and TM3) the majority of p34cdc2 was phosphorylated on tyrosine, in contrast to the p34cdc2 in tumorigenic (TM2H) hyperplasias and tumors. Two-dimensional PAGE analysis of mammary tumor samples with antibodies specific to cdc2, cdk2 and phosphorylated tyrosine revealed one p34cdc2 form, two p33cdk2 isoforms and two phosphotyrosine isoforms of about 33-34 kDa. The results suggest that the high levels of tyrosine phosphorylation in cdc2 and cdk2 reflect the low tumorigenic potential of a subset of mammary preneoplastic hyperplasias. This interpretation is in accord with current concepts on the role of tyrosine phosphorylation in the regulation of the cyclin-dependent kinases.
 ...
PMID:Tyrosine phosphorylation in mouse mammary hyperplasias. 772 75

The tumor suppressor protein p53 is phosphorylated at a C-terminal residue (serine 386 in mouse p53) by the protein kinase CK2. Phosphorylation by CK2 activates the specific DNA binding function of p53 and stimulates its ability to suppress cellular growth. Previous reports have suggested that phosphorylation of p53 at the CK2 site is stimulated in cells expressing the large tumor antigen (T antigen) of simian virus 40 (SV40). To test this idea, we have expressed a C-terminal p53 "mini-protein" which comprises amino acids 154-387 of mouse p53 and therefore lacks the heavily phosphorylated N-terminus. In addition, the serine 309 phosphorylation site (targeted by cyclin-dependent kinases) has been mutated to encode alanine. We have expressed the p53 mini-protein in mammalian cells and shown by phosphopeptide mapping that it is phosphorylated at a single physiological phosphorylation site, serine 386. Using this mini-protein as a cellular target for CK2, we have shown that phosphorylation of p53 by CK2 is not affected by the presence of T antigen. The p53 mini-protein is likely to be a useful tool with which to probe the regulation of p53 phosphorylation by CK2 in response to other factors which influence cell growth.
 ...
PMID:A novel system to investigate the phosphorylation of the p53 tumor suppressor protein by the protein kinase CK2. 773 30

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.
 ...
PMID:Cyclin D1 is dispensable for G1 control in retinoblastoma gene-deficient cells independently of cdk4 activity. 773 41

Temporally orderly activation of cyclin-dependent kinases (Cdks) governs progression and transitions of the cell cycle in eukaryotic cells. Binding of Cdks to cyclins and threonine phosphorylation in the Cdks are required to form fully active holo-Cdks. So far, 8 types of cyclins and 7 Cdks are known in mammals. Two types of the cyclins, D-(D1, D2, D3) and E-type cyclins, function in the G1 phase of the cell cycle. D-type cyclins form active complexes with Cdk 4 or Cdk 6 earlier than E-type cyclin does with Cdk 2. Overexpression of the cyclin D1 has been reported in human tumors including parathyroid adenomas with chromosomal abnormality, suggesting that overexpression of the cyclin D1 could abrogate cell cycle control in G1 phase and may contribute to generate tumor cells.
 ...
PMID:[Cell cycle and parathyroid tumor]. 775 70

The combination of recombinant human fibroblast interferon (IFN-beta) and the antileukemic compound mezerein (MEZ) induces terminal differentiation with an irreversible loss of proliferative capacity in human melanoma cells. Using subtraction hybridization, cDNAs were identified that display enhanced expression in terminally differentiated and growth arrested human melanoma cells (Jiang and Fisher, 1993; Jiang et al., 1994a). A specific melanoma differentiation-associated (mda) cDNA, mda-6, is described whose expression inversely correlates with melanoma progression and growth. mda-6 is identical to WAF1/CIP1/SDI1 that encodes the M(r) 21,000 protein (p21) that is an inhibitor of cyclin-dependent kinases. Actively growing normal melanocyte, SV40-immortalized human melanocyte and dysplastic nevus cell lines synthesize elevated levels of mda-6 mRNA; whereas, actively proliferating radial and early vertical growth phase primary melanomas as well as metastatic human melanoma cells produce reduced levels of mda-6 mRNA. Treatment of primary and metastatic human melanoma cells with IFN-beta + MEZ results in growth inhibition and an increase in mda-6 expression. mda-6 expression also increases when human melanoma cells are grown to high saturation densities or when grown in serum-free medium. Using anti-p53 and anti-p21 antibodies, an inverse correlation is found between p53 and p21 protein levels during growth arrest and differentiation. Induction of growth arrest and terminal differentiation in H0-1 human melanoma cells by IFN-beta + MEZ results in a temporal decrease in wild-type p53 protein levels with a corresponding increase in p21 levels. In the Matrigel-assisted melanoma progression model, mda-6 expression decreases in early vertical growth phase primary human melanoma cells selected for autonomous or enhanced tumor formation in nude mice. In metastatic human melanoma cells displaying a loss of metastatic potential resulting from introduction of a normal human chromosome 6, mda-6 mRNA levels increase. Taken together, these studies indicate that mda-6 (p21) may function as a negative regulator of melanoma growth, progression and metastasis.
 ...
PMID:The melanoma differentiation-associated gene mda-6, which encodes the cyclin-dependent kinase inhibitor p21, is differentially expressed during growth, differentiation and progression in human melanoma cells. 775 61

It has recently become clear that cyclin-dependent kinase (cdk) complex regulates the cell cycle by phosphorylating Rb protein, a tumor suppressor protein. It is likely that this complex is a target of various growth factors and anti-growth factors (UV, TGF-beta etc.) in keratinocyte (KC). It has also been suggested that abnormalities in the cell cycle regulating mechanism such as increased activity of cyclin-cdk due to mutation of p53, a tumor suppressor gene, and overexpression of cyclin D may be concerned with carcinogenesis of KC. Thus, recent studies indicate that the cyclin-cdk complex is a common target of proliferation and carcinogenesis in KC.
 ...
PMID:Cell cycle regulators in the keratinocyte (cyclin-cdk). 775 27

The tumor suppressor gene p53 is involved in controlling cell cycle checkpoint or triggering apoptosis. p53 may accomplish these roles by acting as a sequence-specific transcription factor. One of the downstream targets of p53 transcription control is the WAF1/CIP1 gene, whose gene product p21 interacts with several cyclins and cyclin-dependent kinases, resulting in inhibition of these kinases. In our previous studies, we have shown that the p53 protein level in mouse keratinocytes was elevated following UV-B/A irradiation. In this paper we further investigated the consequences of increased p53 protein level by characterizing p53 DNA-binding level and WAF1/CIP1 gene expression in UV-B/A-irradiated mouse keratinocytes. Consistent with the increased level of p53 protein, both p53 DNA-binding level and steady-state level of WAF1/CIP1 mRNA were elevated. We have demonstrated that the induction of WAF1/CIP1 mRNA was mediated by p53, since no WAF1/CIP1 induction was observed in p53-deficient cells upon UV-B exposure. These observations suggest an important role for the tumor suppressor gene p53 in the response of keratinocytes to the biologically relevant UV-B/A irradiation and in suppressing UV-induced skin cancer.
 ...
PMID:UV-B/A irradiation of mouse keratinocytes results in p53-mediated WAF1/CIP1 expression. 776 Oct 96

Cyclins are regulatory subunits of the cyclin dependent kinases (CDKs), the enzymes that drive the cell through the respective phases and check-points of the cell cycle. The expression of cyclins in non-tumor cells, regulated by timely induction of their synthesis and proteolysis, is scheduled, occurring at discrete periods of the cell cycle. Using multiparameter flow cytometry we have recently observed that expression of cyclins B1 and E in individual normal lymphocytes mitogenically stimulated by phytohemagglutinin (PHA) and lymphocytic leukemic MOLT-4 cells was similar, restricted to particular phases of the cycle: cyclin B1 was detected only in G2+M- and cyclin E in late G1 and early S-phase cells. In the present study we have measured the expression of cyclins A, D2 and D3 in these cells. The presence of cyclin A was restricted to late S and G2 phases, both in the case of lymphocytes and of MOLT-4 cells. Over 95% of the non-stimulated lymphocytes were both cyclin D2 and D3 negative. Mitogenic stimulation with PHA-induced expression of cyclins D2 and D3 in over 50% cells, which corresponds to the percentage of cells that respond to this mitogen in cultures. Expression of these proteins peaked between 8 and 24 h after addition of PHA, and then decreased at the time of cell entrance to S. During exponential growth (48-72 h after stimulation with PHA) expression of the D-type cyclins was diminished: only between 5-10% of the lymphocytes had levels of cyclin D3 as high as G1 cells between 8-24 h after PHA stimulation. Populations of proliferating lymphocytes and MOLT-4 cells were very heterogeneous in terms of expression of D-type cyclins by individual cells. While expression of cyclin D2 in exponentially growing MOLT-4 cells was similar to that of proliferating lymphocytes, the percent of cells expressing cyclin D3 as well as the degree of expression, was higher in MOLT-4 cells, regardless of the phase of the cycle. These results, with our earlier observations of the untimely expression of cyclins B1 and E in several other tumor lines, suggest that altered expression of cyclins may be a frequent feature of malignancy.
 ...
PMID:Expression of cyclins A, D2 and D3 in individual normal mitogen stimulated lymphocytes and in MOLT-4 leukemic cells analyzed by multiparameter flow cytometry. 776 53

It is important to know the proliferating ability and the malignant potential of tumor tissues. We have examined the expression of PCNA/cyclin, p53 and C-erbB-2 in transitional cell carcinoma of the human urinary bladder by an immunohistochemical method, and compared the results with the histological grade, stage and survival rate. Immunohistochemical studies, using monoclonal and polyclonal antibodies, on these proteins were performed with formaline fixed-paraffin sections of tumor tissue from 40 patients with bladder cancer. Generally, a higher grade and higher stage tumors expressed PCNA/cyclin, p53 and C-erbB-2 with a greater frequency than the tumors with a lower grade and lower stage and strongly stained cases had a lower survival rate than weakly stained cases. These findings suggest that the detection of each antigen is useful for estimating the malignant potential of transitional cell carcinoma as the adjuvant studies, because of its applicability to paraffin-embedded tissue sections and its simple, rapid technique.
 ...
PMID:[Expression of PCNA/cyclin, p53, C-erbB-2 versus histological grade in transitional cell carcinoma of urinary bladder]. 778 54

The 9p21 locus has been deleted at a high frequency in a wide variety of tumors. Recently, two genes, p16INK4A and p15INK4B (also called MTS1 and MTS2), have been localized in close proximity at the 9p21 locus, encoding cyclin-dependent kinases 4/6 inhibitors of relative molecular mass 16 kD and 15 kD, respectively and also found to be deleted at a high frequency in tumor cell lines. We analyzed p16INK4A and p15INK4B genes in 178 cases of primary leukemias including 81 cases of chronic lymphocytic leukemia (CLL), seven of hairy cell leukemia (HCL), seven of chronic myelogenous leukemia (CML), 43 of acute myelogenous leukemia (AML), 27 of acute lymphoblastic leukemia (ALL), and 13 of myelodysplastic syndrome (MDS) by Southern blot analyses. The ALL cases showed a relatively high frequency of homozygous deletions (22%, 6 of 27) at the p16INK4A gene locus. Interestingly, of the six cases with p16INK4A homozygous deletions, only three showed homozygous deletions at the p15INK4B gene. In 81 CLL patients, we detected one homozygous and five heterozygous deletions at both the p16INK4A and p15INK4B genes and two heterozygous deletions at the p16INK4A gene alone. Deletion of these two genes in AML cases is relatively low (9%). We did not detect deletions in any of the MDS, HCL, and CML cases examined. Sequence analyses of p16INK4A gene of six CLL cases with heterozygous deletion at this locus showed a 27-bp deletion at the splice acceptor site of intron 1 in one case and changes in the coding sequence in three other cases. The data presented in this report showed that (1) p16INK4A and p15INK4B genes are preferentially deleted homozygously in ALL and heterozygously in CLL cases with frequent mutation in the second allele, and (2) p16INK4A gene appears to be more frequently deleted than p15INK4B gene.
 ...
PMID:p16INK4A and p15INK4B gene deletions in primary leukemias. 779 38


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