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

Radioimmunotherapy (RIT) in breast cancer patients using I-131-chimeric L6 (ChL6) and in human breast cancer xenografts in nude mice using Y-90-1,4,7,10-tetraazacylododecant N,N',N",N"'-tetraacetic acid-peptide ChL6 (Y-90-ChL6) has shown promise. Tumor cell response to low-dose rate (5-25 rads/h) irradiation from Y-90-ChL6 RIT, therefore, was correlated with levels of tumor cell mRNA for selected genes linked to programmed cell death (apoptosis). Three groups of 10-16 mice with 1-2 HBT 3477 xenograft tumors were treated with 100, 150, or 250 microCi Y-90-ChL6. Three tumors were taken before and two tumors each were taken 3, 6, and 24 h after injection of 150 microCi Y-90-ChL6. Tumor expression of mRNA was amplified by PCR for p53, PIC1, c-myc, and transforming growth factor-beta 1; quantitated; and standardized to N-ras. Tumors received radiation doses of 2000, 3000, and 5000 rads, respectively, for the groups of mice that received 100, 150, and 250 microCi Y-90-ChL6, and tumor regression occurred in each group, with mean tumor volumes decreased by 10, 50, and 95% at nadir after Y-90-ChL6 injection. At the highest dose level, 30% of mice had complete remissions, and no treatment deaths occurred, although tumors subsequently recurred. Continuous up-regulation of transforming growth factor-beta 1 and c-myc mRNA expression was observed from 3 to 24 h after treatment. Expression of p53 and PIC1 increased at 3 h and subsequently decreased to the untreated control levels. These observations are consistent with previous observations of early responses of p53 and PIC1 to cellular DNA damage and subsequent G1 cell cycle arrest or apoptosis. Apoptosis-associated gene expression patterns observed in this tumor model provide evidence that changes are initiated in the first 24 h of RIT associated with radiation doses of 100-700 rads. These preliminary data suggest that insight into the molecular basis of RIT-induced tumor regression may be gained by further studies using different radiation doses.
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PMID:Yttrium-90 chimeric L6 therapy of human breast cancer in nude mice and apoptosis-related messenger RNA expression. 749 56

Human UBC9 is a member of the E2 (ubiquitin conjugation enzyme) family of proteins. Instead of conjugating to ubiquitin, it conjugates with a ubiquitin homologue UBL1 (also known as SUMO-1, GMP1, SMTP3, PIC1, and sentrin). UBC9 has been shown to be involved in cell cycle regulation, DNA repair, and p53-dependent processes. The binding interfaces of the UBC9 and UBL1 complex have been determined by chemical shift perturbation using nuclear magnetic resonance spectroscopy. The binding site of UBL1 resides on the ubiquitin domain, and the binding site of UBC9 is located on a structurally conserved region of E2. Because the UBC9-UBL1 system shares many similarities with the ubiquitin system in structures and in conjugation with each other and with target proteins, the observed binding interfaces may be conserved in E2-ubiquitin interactions in general.
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PMID:The binding interface between an E2 (UBC9) and a ubiquitin homologue (UBL1). 1035 47

Sumoylation of p53 by the ubiquitin-like protein, SUMO-1/sentrin/PIC1, has been shown to stimulate its transcriptional activation activity. The SUMO E3 ligase, a key enzyme in the recognition of substrates to be sumoylated, has not yet been identified. We isolated PIAS1 (protein inhibitor of activated STAT1) as a SUMO-1 binding protein by yeast two-hybrid screening. In addition, PIAS1 bound p53 and Ubc9, the E2 for SUMO. PIAS1 that was mutated in the RING finger-like domain bound p53 and SUMO-1, but not Ubc9. PIAS1 catalyzed the sumoylation of p53 both in U2OS cells and in vitro in a domain-dependent manner. These data suggest that PIAS1 functions as a SUMO ligase, or possibly as a tightly bound regulator of it, toward p53.
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PMID:Involvement of PIAS1 in the sumoylation of tumor suppressor p53. 1158 32

Human Ubc9 is homologous to ubiquitin-conjugating enzymes. However, instead of conjugating ubiquitin, it conjugates a ubiquitin homologue, small ubiquitin-like modifier 1 (SUMO-1), also known as UBL1, GMP1, SMTP3, PIC1, and sentrin. The SUMO-1 conjugation pathway is very similar to that of ubiquitin with regard to the primary sequences of the ubiquitin-activating enzymes (E1), the three-dimensional structures of the ubiquitin-conjugating enzymes (E2), and the chemistry of the overall conjugation pathway. The interaction of substrates with Ubc9 has been studied using NMR spectroscopy. Peptides with sequences that correspond to those of the SUMO-1 conjugation sites from p53 and c-Jun both bind to a surface adjacent to the active site Cys93 of human Ubc9, which has been previously shown to include residues that demonstrate the most significant dynamics on the microsecond to millisecond time scale. Mutations in this region, Q126A, Q130A, A131D, E132A, Y134A, and T135A, were constructed to evaluate the role of these residues in SUMO-1 conjugation. These alterations have significant effects on the conjugation of SUMO-1 with the target proteins p53, E1B, and promyelocytic leukemia protein and define a substrate binding site on Ubc9. Furthermore, the SUMO-1 conjugation site of p53 does not form any defined secondary structure when either free or bound to Ubc9. This suggests that a defined secondary structure at SUMO-1 conjugation sites in target proteins is not necessary for recognition and conjugation by the SUMO-1 pathway.
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PMID:Identification of a substrate recognition site on Ubc9. 1187 16

Entry into the cell cycle is governed by cyclins, cyclin-dependent kinases (CDKs) and CDK-inhibitors (CDKIs). The p53-regulated inhibitor of CDKs (PIC1) is a universal CDKI whose gene expression is directly induced by the p53 tumor suppressor protein. Reverse transcription and polymerase chain reaction revealed strong PIC1 gene expression in control MRC-5 human embryo lung cells, but relatively weaker bands in A549 lung carcinoma; Hep3B, Mahlavu, PLC/PRF/5 hepatocellular carcinoma; SiHa, CaSki, HeLa cervical carcinoma; T24 bladder carcinoma; MCF7 breast carcinoma; Raji Burkitt lymphoma; HT-1080 fibrosarcoma; and G-401 Wilms' tumor cell lines. These data are consistent with other results obtained by Northern and Western blot and immunoprecipitation techniques, indicating diminished PIC1 expression in cancer cells especially those harboring mutated p53, or human papillomavirus E6 oncoproteins which abrogate p53 activity. PIC1 gene expression was absent in the Molt-4 T-lymphoblastic leukemia cell line with a previously documented alternatively-spliced p53 transcript translating into p53 protein truncated at the carboxyl terminus. It is proposed that this aberrant p53 interferes with the binding of wild-type p53 and other transcription factors to the PIC1 promoter thereby abolishing PIC1 gene expression. This Molt-4 cell line could serve as a useful experimental system for studying the interaction between p53 and other cellular factors with the PIC1 gene. Single-strand conformation polymorphism and direct cycle DNA sequencing analyses demonstrated a PIC1 variant (with an AGC to AGA substitution at codon 31 culminating in a serine to arginine replacement) in Mahlavu, PLC/PRF/5, SiHa, A549 and Raji cell lines. The higher proportion of the PIC1 variant in cancer cell lines (5/13 or 38%) compared with normal individuals (14%), coupled with differences between the predicted secondary structures of the normal and variant PIC1 proteins merit further investigations to elucidate the biological significance of this variant.
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PMID:The gene encoding the p53-regulated inhibitor of cdks (pic1) is not expressed in the molt-4 leukemia-cell line with p53 truncated at the carboxyl-terminus, and harbors a nucleotide substitution at codon-31 in several other cancer cell-lines. 2155 14