Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PIBF was previously identified as a 34 kDa immunomodulatory molecule secreted by pregnancy lymphocytes and is thought to play a crucial role in preventing rejection of the embryo by the maternal immune response. Recent data suggested that PIBF protein was also expressed by the progesterone receptor (PR) positive MCF-7 breast tumor cell line. Therefore our study was designed to analyze the expression of PIBF in malignant cell lines and primary tumors both at the mRNA and protein levels. RNA expression analyses of several human cell lines with different tissue origin and paired human tumor/normal tissues, as well as of several PR+ and PR- breast tumors revealed that PIBF mRNA was overexpressed in highly proliferating cells independent of the presence of PR. In addition to the full-length PIBF mRNA encoding for a 90 kDa protein, several alternatively spliced species were detected, all resulting from perfect exon skipping. The most frequently identified splice variant is predicted to encode for an approximately 35 kDa protein. Immunofluorescence microscopy revealed a centrosomal localization for the full-length PIBF, while the 35 kDa form showed a diffuse cytoplasmic staining. These data, together with the identification of the PIBF gene in the chromosomal region associated with breast cancer susceptibility, reveal a strong parallel with known tumor suppressor proteins, such as BRCA1 and p53 having the same centrosomal localization. Given the notion that a number of proteins shown to be involved in tumorigenesis are associated with the centrosome and disturbed centrosome function causes unequal segregation of chromosomes, studies to evaluate whether or not PIBF that is highly expressed in tumors is directly involved in tumorigenesis are thus warranted.
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PMID:PIBF (progesterone induced blocking factor) is overexpressed in highly proliferating cells and associated with the centrosome. 1530 75

The MDM2 proto-oncogene, which encodes a protein that binds to the p53 tumour suppressor, has been found amplified and overexpressed in a range of human tumours. Although the human MDM2 cDNA sequence has been reported, the genomic organisation of the human gene has not been documented. We have previously reported the detection of five alternative internally deleted MDM2 transcripts in human tumours and suggested these may represent alternatively spliced forms. Here we demonstrate two novel MDM2 transcripts with internal deletions, using RT-PCR followed by sequencing. To definitively ascribe these variant transcript forms to alternative splicing, and to explore associated mechanisms, we have determined the intron--exon organisation of the human genomic sequence. The human MDM2 gene spans approximately 33 kb and is divided into 12 exons. Exon sizes range from 50 to > or =1161 bp and intron sizes vary from 121 to approximately 7000 bp. The positions of intron--exon boundaries are compared with the deletion junctions of the multiple-sized transcripts and discussed in relation to alternative splicing mechanism.
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PMID:Genomic organisation of the human MDM2 oncogene and relationship to its alternatively spliced mRNAs. 1531 25

Prostate cancer is a leading and increasingly prevalent cause of cancer death in men. Whereas family history of disease is one of the strongest prostate cancer risk factors and suggests a hereditary component, the predisposing genetic factors remain unknown. We first showed that KLF6 is a tumor suppressor somatically inactivated in prostate cancer and since then, its functional loss has been further established in prostate cancer cell lines and other human cancers. Wild-type KLF6, but not patient-derived mutants, suppresses cell growth through p53-independent transactivation of p21. Here we show that a germline KLF6 single nucleotide polymorphism, confirmed in a tri-institutional study of 3,411 men, is significantly associated with an increased relative risk of prostate cancer in men, regardless of family history of disease. This prostate cancer-associated allele generates a novel functional SRp40 DNA binding site and increases transcription of three alternatively spliced KLF6 isoforms. The KLF6 variant proteins KLF6-SV1 and KLF6-SV2 are mislocalized to the cytoplasm, antagonize wtKLF6 function, leading to decreased p21 expression and increased cell growth, and are up-regulated in tumor versus normal prostatic tissue. Thus, these results are the first to identify a novel mechanism of self-encoded tumor suppressor gene inactivation and link a relatively common single nucleotide polymorphism to both regulation of alternative splicing and an increased risk in a major human cancer.
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PMID:A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. 1573 5

p73, a member of the p53 family, is expressed from two separate promoters, generating TA and DeltaN variants. Each variant potentially encodes at least seven alternatively spliced isoforms (alpha-eta). Interestingly, we and others have shown that the alpha isoform of p73 has a weaker transcriptional activity than the beta isoform. Because the alpha isoform has an extended C terminus consisting of a sterile alpha motif (SAM) and an extreme C terminus, it appears that the C terminus is inhibitory. However, how the C terminus inhibits the transcriptional activity of p73 has not been determined. Here, we found that both the SAM and the extreme C terminus exert their inhibitory activity by preventing the accessibility of p300/CBP to the activation domain in p73. Specifically, we showed that the SAM and the extreme C terminus together or individually are capable of repressing the function of p73 activation domain, but neither interacts directly with the activation domain, or suppresses the DNA-binding activity, of the p73 protein. We also showed that the intact state of the SAM and the extreme C terminus is essential for their inhibitory functions such that a small deletion of either the SAM or the extreme C terminus abolishes its inhibitory activity. Furthermore, we showed that both inhibitory domains in the C terminus are capable of suppressing the function of a cis heterologous activation domain from p53 or Gal4. Finally, we showed that both inhibitory domains suppress the ability of p73 to interact with the transcriptional coactivators p300/CBP that are necessary for the initiation of transcription.
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PMID:The C-terminal sterile alpha motif and the extreme C terminus regulate the transcriptional activity of the alpha isoform of p73. 1576 43

The archetypal human tumor suppressor p53 is considered to have unique transactivation properties. The assumption is based on the fact that additionally identified human p53 isoforms lack transcriptional activity. However, we provide evidence for the existence of an alternatively spliced p53 isoform (Deltap53) that exerts its transcriptional activity independent from p53. In contrast to p53, Deltap53 transactivates the endogenous p21 and 14-3-3sigma but not the mdm2, bax, and PIG3 promoter. Cell cycle studies showed that Deltap53 displays its differential transcriptional activity only in damaged S phase cells. Upon activation of the ATR-intra-S phase checkpoint, Deltap53, but not p53, transactivates the Cdk inhibitor p21. Induction of p21 results in downregulation of cyclin A-Cdk activity and accordingly attenuation of S phase progression. Data demonstrate that the Deltap53-p21-cyclin A-Cdk pathway is crucial to facilitate uncoupling of repair and replication events, indicating that Deltap53 is an essential element of the ATR-intra-S phase checkpoint.
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PMID:A novel human p53 isoform is an essential element of the ATR-intra-S phase checkpoint. 1616 67

TP53INP1 is an alternatively spliced gene encoding two nuclear protein isoforms (TP53INP1alpha and TP53INP1beta), whose transcription is activated by p53. When overexpressed, both isoforms induce cell cycle arrest in G1 and enhance p53-mediated apoptosis. TP53INP1s also interact with the p53 gene and regulate p53 transcriptional activity. We report here that TP53INP1 expression is induced during experimental acute pancreatitis in p53-/- mice and in cisplatin-treated p53-/- mouse embryo fibroblasts (MEFs). We demonstrate that ectopic expression of p73, a p53 homologue, leads to TP53INP1 induction in p53-deficient cells. In turn, TP53INP1s alters the transactivation capacity of p73 on several p53-target genes, including TP53INP1 itself, demonstrating a functional association between p73 and TP53INP1s. Also, when overexpressed in p53-deficient cells, TP53INP1s inhibit cell growth and promote cell death as assessed by cell cycle analysis and colony formation assays. Finally, we show that TP53INP1s potentiate the capacity of p73 to inhibit cell growth, that effect being prevented when the p53 mutant R175H is expressed or when p73 expression is blocked by a siRNA. These results suggest that TP53INP1s are functionally associated with p73 to regulate cell cycle progression and apoptosis, independently from p53.
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PMID:TP53INP1 is a novel p73 target gene that induces cell cycle arrest and cell death by modulating p73 transcriptional activity. 1604 47

The cellular and molecular pathways of dengue infection have not been as intensively studied compared to the host immunological responses. Changes in mRNA expression levels of ECV304 human endothelial-like cells following infection with the virulent New Guinea C strain of dengue virus type 2 were analyzed by a microarray system comprising 7600 oligonucleotide cDNAs. After normalization against the uninfected control using two independent software programs, 111 genes exhibited at least a 1.5-fold difference in expression level. Out of these, 21 mRNAs were upregulated while 90mRNAs were downregulated. Quantitative real-time RT-PCR was then performed to determine the expression patterns of 15 selected genes of interest involved in the cell cycle (MAD3), apoptosis (RIPK3, PDCD8), cellular receptors (H963, CCR7, KLRC3), transcriptional regulation (RUNX3, HNF4G, MIZ1), signal transduction (HSP27, TRIP, MAP4K4), enzymes (angiotensinogen), protein transport (AP4M1), and cytoskeleton (ACTA2). Dengue virus infection resulted in the downregulation of the C-terminal alternatively spliced p53 variant, the pro-apoptotic IG20 and IG20-SV2 isoforms, and the Fas apoptosis inhibitory molecule (FAIM). Most of the real-time RT-PCR data showed concordance with the normalized microarray data. Hence, real-time RT-PCR validation of high-throughput gene microarray screening is important and necessary before further conclusions on gene expression can be drawn. This study elucidated novel information on the complex responses at the transcriptional level in susceptible human endothelial-like cells induced by a virulent dengue virus strain implicated in the pathogenesis of dengue and/or its complications.
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PMID:Microarray and real-time RT-PCR analyses of a novel set of differentially expressed human genes in ECV304 endothelial-like cells infected with dengue virus type 2. 1611 53

The HDM2 oncoprotein is a cellular inhibitor of p53 and is frequently deregulated in human cancer. However, the HDM2 gene encodes alternatively spliced variants whose functional significance is poorly understood. We had previously reported the detection of alternative HDM2 forms in Hodgkin's lymphoma (HL)-derived cell lines. Here, we have cloned several of these transcripts, including the previously described HDM2-A, -B and -C (which encode the COOH terminus of HDM2), and two novel variants (HDM2-HL1 and -HL2) containing a complete p53 interaction domain. Real-time PCR assays demonstrated that HDM2-A and -B were selectively expressed by HL cell lines and primary tumors, compared with their non-neoplastic counterparts. In transient transfection experiments, alternatively spliced HDM2 isoforms were partially or totally localized within the cytoplasm. HDM2-HL2 was able to inhibit transactivation of a p53-inducible reporter construct and induced a partial relocalization of p53 to the cytoplasm. Expression of HDM2-A and -B caused the activation of p53/p21 and induced growth arrest in primary cells, but also increased the expression levels of cyclins D1 and E. Other possible genes regulated by HDM2-A and -B were identified using cDNA microarray technology. These results imply that HDM2 isoforms may have multiple effects on cell cycle control, and provide insight into the mechanisms through which these molecules contribute to tumorigenesis.
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PMID:Hodgkin's lymphoma cells express alternatively spliced forms of HDM2 with multiple effects on cell cycle control. 1633 Dec 55

Alternative splicing produces more than one protein from the majority of genes and the rarer forms can have dominant functions. Instability of alternative transcripts can also hinder the study of regulation of gene expression by alternative splicing. To investigate the true extent of alternative splicing we have developed a simple method of enriching alternatively spliced isoforms (EASI) from PCRs using beads charged with Thermus aquaticus single-stranded DNA-binding protein (T.Aq ssb). This directly purifies the single-stranded regions of heteroduplexes between alternative splices formed in the PCR, enabling direct sequencing of all the rare alternative splice forms of any gene. As a proof of principle the alternative transcripts of three tumour suppressor genes, TP53, MLH1 and MSH2, were isolated from testis cDNA. These contain missing exons, cryptic splice sites or include completely novel exons. EASI beads are stable for months in the fridge and can be easily combined with standard protocols to speed the cloning of novel transcripts.
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PMID:EASI--enrichment of alternatively spliced isoforms. 1695 Dec 90

The tumor suppressor protein p53 is a transcription factor that induces G(1) arrest of the cell cycle and/or apoptosis. The murine double-minute protein MDM2 and its homologue MDM4 (also known as MDMX) are critical regulators of p53. Altered transcripts of the human homologue of mdm2, MDM2, have been identified in human tumors, such as invasive carcinoma of the breast, lung carcinoma, and liposarcoma. MDM2 alternate forms act to negatively regulate the normal MDM2 gene product, thus activating p53. Although many reports have documented a plethora of tumor types characterized by MDM2 alternative transcripts, few have investigated the signals that might initiate alternative splicing. We have identified a novel role of these alternative MDM2 transcripts in the normal surveillance mechanism of the cell and in DNA damage response. We report that alternate forms of MDM2 are detected after UV irradiation. Furthermore, we show that mouse cells treated with UV are also characterized by alternative transcripts of mdm2, suggesting that this is an important and evolutionarily conserved mechanism for regulating the expression of MDM2/mdm2. An additional p53 regulator and mdm2 family member, MDM4, is likewise alternatively spliced following UV irradiation. By activating alternative splicing of both MDM2 and MDM4, yet another layer of p53 regulation is initiated by the cells in response to damage. A stepwise model for malignant conversion by which alternate forms of MDM2 and MDM4 place selective pressure on the cells to acquire additional alterations in the p53 pathway is herein proposed.
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PMID:Genotoxic stress induces coordinately regulated alternative splicing of the p53 modulators MDM2 and MDM4. 1701 6


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