Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SDI1 is an inhibitor of DNA synthesis that we isolated by expression screening cDNAs prepared from senescent, terminally nondividing human cells. Other groups then cloned this gene as a cyclin-dependent kinase (cdk)-interacting protein (CIP1, p21) that inhibits cdks; the gene was also isolated by screening for genes transactivated by p53 (WAF1). p53 levels are low in senescent and quiescent contact-inhibited or serum-deprived normal human cells, which we have found express high levels of SDI1 mRNA. This indicates that alternate pathways for upregulation of message level of this gene may exist. We therefore proceeded with the study presented here, treating human cells with a variety of growth-arrest-inducing agents, including some that damaged DNA, and found that RNA levels of SDI1 were increased in all cases that resulted in growth inhibition. More important, with the exception of gamma-radiation, most of these agents were able to elevate SDI1 message levels in cells lacking wild-type p53. At least two distinct kinetic profiles for RNA induction were observed, one that implicated p53 transactivation and occurred early enough to cause arrest, and another that clearly was p53 independent and suggested a role for the SDI1 gene product in the maintenance rather than in the cause of inhibition of DNA synthesis.
Mol Carcinog 1994 Oct
PMID:Evidence for a p53-independent pathway for upregulation of SDI1/CIP1/WAF1/p21 RNA in human cells. 752 62

Several groups have recently isolated and characterized an inhibitor of cyclin-dependent kinases, p21CIP1/WAF1 which is transcriptionally induced by wild-type but not mutant p53. It is likely that p21CIP1/WAF1 mediates the growth suppression effects of p53 by arresting the cell cycle at the G1/S checkpoint, and by inducing apoptosis. To test the hypothesis that primary human tumors have mutations in the CIP1/WAF1 gene which propagates the carcinogenic process, we examined primary breast and sarcoma tumor specimens for alterations in the CIP1/WAF1 gene. Unique, or acquired somatic mutations were not observed indicating that they are not selected for during the carcinogenic process; however, two common variants were identified. The variants were not unique to tumors as 10.7% of normal individuals exhibited the variants. Nonetheless, the frequency of the variants in tumors with wild-type p53 (20.4%) was significantly greater (p = 0.05) than in normal DNAs. In contrast, the frequency of the variants (4.1%) was found to be significantly lower in tumors with p53 mutations (p = 0.006). These data suggest that the occurrence of the variants may have a direct effect on tumor development and may, in some cases, be incompatible with p53 mutations.
Hum Mol Genet 1995 Jun
PMID:Two variants of the CIP1/WAF1 gene occur together and are associated with human cancer. 765 64

Cellular physiology has a significant influence on the efficiency of various gene transfer procedures, as shown by the fact that transfection efficiency varies dramatically among different cell lines. However, the aspects of cellular physiology which influence the transfection process remain substantially uncharacterized. In this study, NIH3T3 cells were treated with inhibitors of protein synthesis, DNA synthesis, and RNA synthesis to determine the importance of these processes in the calcium-phosphate transfection process. The results suggest that protein synthesis during the first 4 h after DNA addition enhances transfection. In contrast, inhibition of RNA synthesis has no effect on transfection during the first 24 h post-DNA addition. The DNA synthesis inhibitor results remain inconclusive due to a secondary inhibition of an unknown cellular factor. Secondly, agents that destabilize microtubules, microfilaments, and the golgi apparatus were used to determine whether these elements play a role in the transfection process. The results suggest that microtubules are not involved in the transfection process, microfilaments are important but not necessary for the transfection process, and a functional golgi apparatus is essential early in the transfection process. These studies provide a foundation from which further investigations into the cellular processes involved in the uptake and expression of exogenous DNA can proceed.
Mol Cell Biochem 1995 Apr 26
PMID:Aspects of cellular physiology that influence DNA-mediate gene transfer in NIH3T3 cells. 767 36

This brief review examines the strict relationships between cell apoptosis and G1 cyclins. It has been shown that the basic role of G1 cyclins is in regulating G1 progression and G1/S transition (the critical cycle point for cell program decisions, including apoptosis) a fatal program for cells unable to bypass G1/S checkpoint 1. Notably, both of the two giant regulators of checkpoint 1 (i.e., p105RB [retinoblastoma oncosuppressor-encoded protein] and p53 dependent WAF1/CIP1) are influenced by or influence G1 cyclins: cyclin E/cdk2 kinase complexes hyperphosphorylate p105RB, induce E2F release, and free G1 exit. On the other hand, p21-WAF1/CIP1 is an inhibitor of cyclin-dependent kinases blocking cells at G1/S. Thus, G1 cyclin activity appears as a conditio sine qua non for G1 exit and apoptosis escape.
Cell Mol Biol Res 1994
PMID:Apoptosis and the cell cycle. 778 78

The activation of gene transcription in eukaryotic organisms is regulated by sequence-specific DNA-binding proteins as well as by non-DNA-binding proteins. In this report we describe the modulatory functions of a non-DNA-binding protein, SIN3 (also known as SDI1, UME4, RPD1, and GAM2) on the transactivation properties of the human progesterone receptor (hPR), GAL4, and the HAP1 activator in yeast. Our data suggest that SIN3 is a dual function protein. It negatively regulates the transcriptional activities of hPR-A and hPR-B by affecting the N-terminal activation domain (AF1). SIN3 positively regulates the transcriptional activities of GAL4 and the HAP1 activator. However, it has no effect on the transcriptional activities of the human glucocorticoid receptor (hGR) and GCN4. The SIN3 protein contains four copies of a paired amphipathic helix (PAH) motif. Deletion analysis of the SIN3 PAH motifs shows that the PAH3 motif is essential for SIN3-mediated regulation of hPR, GAL4, and the HAP1 activator. In contrast, the PAH1, PAH2, and PAH4 motifs are not required for SIN3-mediated regulation of these activators. Additionally, we examined the mechanism(s) by which the SIN3 protein modulate the activities of various activators. We are unable to demonstrate the direct interaction of SIN3 protein with these activators using the yeast two-hybrid system or co-immunoprecipitation. These data suggest that SIN3 regulates the transactivation functions of hPR, GAL4, and the HAP1 activator by an indirect mechanism.
Mol Gen Genet 1994 Dec 15
PMID:The yeast SIN3 gene product negatively regulates the activity of the human progesterone receptor and positively regulates the activities of GAL4 and the HAP1 activator. 783 Jul 20

The protein kinase-encoding genes RCK1 and RCK2 from Saccharomyces cerevisiae have been identified as suppressors of Schizosaccharomyces pombe cell cycle checkpoint mutations. Upon expression of these genes, radiation resistance is partially restored in S. pombe mutants with checkpoint deficiencies, but not in mutants with DNA repair defects. Some checkpoint mutants are sensitive to the DNA synthesis inhibitor hydroxyurea, and this sensitivity is also suppressed by RCK1 and RCK2. The degree of suppression can be modulated by varying expression levels. Expression of RCK1 or RCK2 in S. pombe causes cell elongation and decelerated growth. Cells expressing these genes have a single nucleus and a 2n DNA content. We conclude that these genes act in S. pombe to prolong the G2 phase of the cell cycle.
Mol Gen Genet 1995 Feb 06
PMID:The RCK1 and RCK2 protein kinase genes from Saccharomyces cerevisiae suppress cell cycle checkpoint mutations in Schizosaccharomyces pombe. 785 16

The yeast SIN3 gene (also known as SDI1, UME4, RPD1, and GAM2) has been identified as a transcriptional regulator. Previous work has led to the suggestion that SIN3 regulates transcription via interactions with DNA-binding proteins. Although the SIN3 protein is located in the nucleus, it does not bind directly to DNA in vitro. We have expressed a LexA-SIN3 fusion protein in Saccharomyces cerevisiae and show that this fusion protein represses transcription from heterologous promoters that contain lexA operators. The predicted amino acid sequence of the SIN3 protein contains four copies of a paired amphipathic helix (PAH) motif, similar to motifs found in HLH (helix-loop-helix) and TPR (tetratricopeptide repeat) proteins, and these motifs are proposed to be involved in protein-protein interactions. We have conducted a deletion analysis of the SIN3 gene and show that the PAH motifs are required for SIN3 activity. Additionally, the C-terminal region of the SIN3 protein is sufficient for repression activity in a LexA-SIN3 fusion, and deletion of a PAH motif in this region inactivates this repression activity. A model is presented in which SIN3 recognizes specific DNA-binding proteins in vivo in order to repress transcription.
Mol Cell Biol 1993 Mar
PMID:Transcriptional repression in Saccharomyces cerevisiae by a SIN3-LexA fusion protein. 844 14

Diploid a/alpha Saccharomyces cerevisiae cells cease mitotic growth and enter meiosis in response to starvation. Expression of meiotic genes depends on the IME1 gene product, which accumulates only in meiotic cells. We report here an analysis of the regulatory region of IME2, an IME1-dependent meiotic gene. Deletion and substitution studies identified a 48-bp IME1-dependent upstream activation sequence (UAS). Activity of the UAS also requires the RIM11, RIM15, and RIM16 gene products, which are required for expression of the chromosomal IME2 promoter and for meiosis. Through a selection for suppressors that permit UAS activity in an ime1 deletion mutant, we identified recessive mutations in three genes, SIN3 (also called RPD1, UME4, and SDI1), RPD3, and UME6 (also called CAR80), that were previously known as negative regulators of other early meiotic genes. Mutational analysis of the IME2 UAS reveals two critical sequence elements: a G+C-rich sequence (called URS1), previously identified at many meiotic genes, and a newly described element, the T4C site, that we found at a subset of meiotic genes. In agreement with prior studies, URS1 mutations lead to elevated IME2 UAS activity in the absence of IME1. However, the URS1 mutations prevent any further stimulation of UAS activity by IME1. Repression through URS1 has been shown to require the UME6 gene product. We find that activation of the IME2 UAS by IME1 also requires the UME6 gene product. Thus, UME6 and the URS1 site both have dual negative and positive roles at the IME2 UAS. We propose that IME1 modifies UME6 to convert it from a negulator to a positive Regulor.
Mol Cell Biol 1993 Apr
PMID:Bipartite structure of an early meiotic upstream activation sequence from Saccharomyces cerevisiae. 845 5

Recent research has yielded a dramatic increase in the number of connections between oncogenesis and the proteins which regulate the cell cycle. Three classes of protein which inhibit the activity of cyclin-dependent kinases (CDKs) have emerged as potential targets for oncogenic inactivation. p16 and related proteins inhibit the cyclin/CDK complexes which regulate the transition from G1 to S phase; numerous studies have revealed that p16 is mutated in most tumor cell lines and in some types of primary tumor. p21/WAF1/Cip 1 and the related p27Kip protein inhibit a broader range of cyclin/CDK complexes than p16. Although the absence of p21/WAF1/Cip1 from cyclin/CDK complexes is correlated with cellular transformation, no mutations in this gene have been found in tumors or tumor-derived cell lines. A third class of genes which are potential targets for oncogenic inactivation are the kinases and phosphatases which regulate the activity of cyclin/CDK complexes by phosphorylation and dephosphorylation of the CDK proteins. Disruption of any of these genes would result in loss of normal regulation of cell growth.
J Mol Med (Berl) 1995 Oct
PMID:Inhibitors of cyclin-dependent kinase and cancer. 858 12

Progression of human melanoma toward increasing malignant behavior is associated with several nonrandom chromosomal aberrations, most commonly involving chromosomes 1, 6, 7, 9, and 10. We previously showed that introduction of human chromosome 6 into the highly metastatic human malignant melanoma cell line C8161 completely suppressed metastasis without altering tumorigenicity (Welch DR, Chen P, Miele ME, et al., Oncogene 9:255-262, 1994). Alterations of chromosome 1 are the most frequent chromosome abnormality observed in melanomas, and they frequently arise late in tumor progression. The purpose of the study presented here was to compare the effects of chromosomes 1 and 6 on malignant melanoma metastasis. By using microcell-mediated chromosome transfer, single copies of neo-tagged human chromosomes 1 or 6 were introduced into the human melanoma cell line MelJuSo. The presence of the added chromosome was verified by G banding of karyotypes, fluorescence in situ hybridization, and screening for polymorphic markers on each chromosome. The incidence and number of metastases per lung after intravenous or intradermal injection of parental MelJuSo cells was significantly (P<0.01) greater than those of hybrids containing either chromosome 1 or chromosome 6, although chromosome 1 was a less potent inhibitor of metastasis than chromosome 6. Cultures established from primary tumors and metastases remained neomycin resistant, suggesting that portions of the added chromosomes were retained. These results strengthen the evidence for the presence of a melanoma metastasis suppressor gene on chromosome 6. neo6/MelJuSo hybrids expressed 2.4- to 3.4-fold more of the melanoma differentiation-associated gene mda-6 (previously shown to be identical to WAF1/CIP1/Sdi1/CAP20) than parental metastatic cells. mda-6/WAF1 is among the candidate genes on chromosome 6. These results also demonstrate, for the first time, the existence of metastasis suppressor genes on human chromosome 1, although these genes appear to be less potent than the one encoded on chromosome 6.
Mol Carcinog 1996 Apr
PMID:Metastasis suppressed, but tumorigenicity and local invasiveness unaffected, in the human melanoma cell line MelJuSo after introduction of human chromosomes 1 or 6. 863 87


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