Purpose: Alterations in the structure of the p53 protein are one of the most common changes associated with human cancers. The CREB-binding protein(CBP) is a transcriptional co-activators of various sequence-specific DNA-binding transcription factors and is involved in a wide variety of cellular activities, such as DNA repair, cell growth, differentiation, and apoptosis. This article examined the expression levels of the p53 protein and CBP as well as their diagnostic value in a biopsy sample. METHODS: Immunohistochemical analysis were performed in 60 hyperplastic polyps, 180 adenomatous polyps, and 120 adenocarcinomas which had sampled from colono-fibroscopic exam from January 2000 to August 2003. RESULTS: 1. p53 protein expression was observed in 15% (9/60) of hyperplastic polyps, in 68.9% (124/180) of adenomatous polyps, and in 80% (96/120) of adenocarcinomas (P<0.01). 2. p53 protein expression according to the cellular atypia in the adenomatous polyp was observed in 45% (27/ 60) of mild dysplasia, 78.3% (47/60) of moderate dysplasia, and 83.4% (50/60) of severe dysplasia. There was an increasing tendency in high grade dysplasia, which is statistically significant (P<0.05). 3. p53 protein expression according to the level of differentiation was observed in 90% (54/60) of well differentiated adenocarcinomas, 78% (39/50) of moderately differentiated adenocarcinomas, and 30% (3/ 10) of poorly differentiated adenocarcinomas (P<0.01). 4. CBP expression was observed in 30% (18/60) of hyperplastic polyps, 70.6% (127/180), of adenomatous polyps, and 85% (102/120) of adenocarcinomas (P<0.01). 5. CBP expression according to cellular atypia in adenomatous polyp was observed in 48.3% (29/60) of mild dysplasia, 76.6% (46/60) of moderate dysplasia, and 86.7% (52/60) of severe dysplasia (P<0.05). 6. CBP expression according to cellular differentiation was observed in 90% (36/60) of well differentiated adenocarcinomas, 86% (43/50) of moderately differentiated adenocarcinomas, and 50% (5/10) of poorly differentiated adenocarcinomas (P<0.05). Conclusion: The p53 protein and CBP expression can indicate the malignant potentiality of the colon cell indirectly.
Adenocarcinoma* ; Adenomatous Polyps ; Apoptosis ; Biopsy ; Colon* ; CREB-Binding Protein* ; DNA Repair ; Humans ; Polyps* ; Transcription Factors

The patient was a girl aged 3 years and 8 months with normal body length and body weight at birth. The girl had feeding difficulty after birth. Her height, body weight, and head circumference were below the 3rd percentile. She had intellectual disability and an unusual facies manifesting as arched shaggy eyebrows, down-slanting palpebral fissures, and broad nasal bridge, but had no a beaked nose, broad thumbs, or big toes. These clinical manifestations were basically consistent with Rubinstein-Taybi syndrome (RSTS). Gene sequencing identified a heterozygous splice site mutation, c.3779T+1G>T, in the CREBBP gene, which did not exist in her parents. Therefore, a definite diagnosis of RSTS was made. The mutation c.3779T+1G>T had not been reported in the Human Gene Mutation Database and was identified as a novel pathogenic mutation. Then the girl was given rehabilitation training for delayed language and motor development. The girl has been followed up for 3 months in the outpatient department, but the effect of rehabilitation treatment has not been evaluated.
CREB-Binding Protein ; genetics ; Child, Preschool ; Female ; Humans ; Mutation ; Rubinstein-Taybi Syndrome ; genetics ; rehabilitation

OBJECTIVE: To summarize the clinical characteristics and identify gene mutations of 2 probands with Rubinstein-Taybi syndrome (RSTS). METHODS: Clinical characteristics of 2 probands with Rubinstein-Taybi syndrome were summarized. Genomic DNA was extracted from peripheral blood samples from the patients and their parents. Genomic DNA was subjected to whole exome next generation sequencing. Suspected variants were confirmed by Sanger sequencing. RESULTS: The two patients were characterized by typical facial features, broad thumbs and big toes, intellectual disability, and postnatal growth retardation. Two variants of the CREBBP gene, namely c.3779+1G>A and c.5052_c.5053insT, were respectively identified in the 2 patients. Among these, c.3779+1G>A was a previously known pathological mutation, while c.5052_c.5053insT was unreported previously. Both variants were predicted to be pathological. CONCLUSION Two cases of Rubinstein-Taybi syndrome were diagnosed, which facilitated the diagnosis and genetic counselling.
CREB-Binding Protein ; genetics ; Genetic Testing ; High-Throughput Nucleotide Sequencing ; Humans ; Phenotype ; Rubinstein-Taybi Syndrome ; genetics

CREB-Binding Protein/genetics* ; Humans ; Lymphangiectasis, Intestinal ; Rubinstein-Taybi Syndrome/genetics*

PURPOSE: The wild-type p53 protein participates in suppressing cell transformations while its mutant forms has tumorigenic potential. Alterations in the structure of the p53 protein are one of the most common changes associated with human cancers. CREB-binding protein (CBP) and its homologue, p300, are transcriptional co-activators of various sequence-specific DNA-binding transcription factors and are involved in a wide range of cellular activities, such as DNA repair, cell growth, differentiation, and apoptosis. Several studies suggested that an association between p53 and p300 might account for the p53-responsible negative regulation. This study examined the relationship between p53 and CBP expression in terms of the clinicopathological factors and significance. METHODS: The level of p53 protein and CBP expression was measured in 150 gastric adenocarcinoma patients, who had undergone a gastrectomy, and the relationship between p53 and CBP was examined. Immunohistochemical stain was performed on formalin-fixed paraffin-embedded sections using monoclonal anti-p53 and anti-CBP antibody. RESULTS: 1. p53 protein was expressed in 46.3% (31/67) of early gastric cancers (EGC), 69.9% (58/83) of advanced gastric cancers (AGC)(P<0.05), 69.1% (65/94) of the intestinal type, 42.9% (24/56) of the diffuse type (P<0.05), 78.5% (55/70) of patients with a lymph node metastasis and 42.5% (34/80) of patients without a lymph node metastasis (P<0.01). 2. CBP expression was observed in 65% (61/94) of intestinal type, 51% (29/56) of the diffuse type (P>0.05), 47.8% (32/67) of EGC, 69.8% (58/83) of AGC (P<0.05), 68.6% (48/70) of patients with a lymph node metastasis and 52.5% (42/80) of patients without a lymph node metastasis (P>0.05). 3. p53 protein and CBP expression was coincidentally observed in 66.7% of gastric adenocarcinomas, and there was a significant correlation between the expression of both (P<0.05). CONCLUSION: That the expression of the p53 protein and CBP indirectly indicate the malignant potential of a cell, and may play an indirect role in the CBP and p53-mediated tumorigenic potential.
Adenocarcinoma* ; Apoptosis ; CREB-Binding Protein* ; DNA Repair ; Gastrectomy ; Humans ; Lymph Nodes ; Neoplasm Metastasis ; Stomach ; Stomach Neoplasms ; Transcription Factors

OBJECTIVETo investigate the clinical and genetic features of 2 patients with Rubinstein-Taybi syndrome.

METHODUsing next generation sequencing (NGS) the CREBBP and EP300 genes of 2 children who were diagnosed as Rubinstein-Taybi syndrome at Peking Union Medical College Hospital. The mutations identified by NGS were verified by PCR were analyzed.

RESULTThe 2 patients at the age of 5 months and 4.5 years manifested short stature (the height were 60 cm and 99 cm respectively), low hairline, thick and dense hair and eyebrows, long lash, epicanthus of both eyes, protruded supercilliary arch, broad and flat thumbs and halluces, and particular facial abnormalities. Patient 2 had language retardation besides. One missense mutation of c.3535A>G, p.Ser1179Gly was found in CREBBP gene in patient 1 and one microdeletion mutation of c.4995_4999delCGCCT, p. Ala1666Pro fs66x was found inpatient 2. Both mutations were reported for the first time.

CONCLUSIONRubinstein-Taybi syndrome is characterized by mental and growth retardation, wide and flat thumbs and first toes, and dysmorphic facial features. CREBBP is one of the causative genes. Mutation detection on CREBBP gene can confirm the diagnosis of Rubinstein-Taybi syndrome.

CREB-Binding Protein ; genetics ; Child ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Mutation ; genetics ; Mutation, Missense ; Rubinstein-Taybi Syndrome ; diagnosis ; genetics

Rubinstein-Taybi syndrome (RTS) is a congenital disorder characterized by typical facial features, broad thumbs and toes, with mental retardation. Additionally, tumors, keloids and various congenital anomalies including congenital heart defects have been reported in RTS patients. In about 50% of the patients, mutations in the CREB binding protein (CREBBP) have been found, which are understood to be associated with cell growth and proliferation. Here, we describe a typical RTS patient with Arnold-Chiari malformation. A mutation in the CREBBP gene, c.4944_4945insC, was identified by mutational analysis.
Arnold-Chiari Malformation ; Congenital, Hereditary, and Neonatal Diseases and Abnormalities ; CREB-Binding Protein ; Heart Defects, Congenital ; Humans ; Intellectual Disability ; Keloid ; Rubinstein-Taybi Syndrome ; Thumb ; Toes

OBJECTIVETo observe the changes in the learning and memory functions and the hippocampal expression of phosphorylated cAMP response element-binding protein (pCREB) in rats with status epilepticus and generalized nonconvulsive status epilepticus.

METHODSStatus epilepticus (SE) and generalized nonconvulsive status epilepticus (GNCSE) was induced by pentylenetetrazol kindling in SD rats, and the learning and memory function changes of the kindled rats were assessed by means of Morris water-maze test and Y-maze test with alternative electric stimulation. Immunocytochemistry was used for analysis pCREB protein expression in the hippocampus of the rats.

RESULTSIn Morris water-maze test, the rats with SE showed prolonged mean escape latency (P<0.05), shortened swimming time in the platform quadrant (P<0.05), and reduced number of times of platform crossing (P<0.05) in the short term after kindling. But these changes were reversed and became normal a month after the kindling (P>0.05). In the Y-maze test with alternative electric stimulation, the total error (TE) of SE rats increased significantly in the short term after epilepsy (P<0.05), but recovered the normal level a month after kindling (P>0.05). The GNCSE rats showed prolonged mean escape latency at only certain time periods (P<0.05) in the short term, but with swimming time in the platform quadrant and number of platform crossings similar to the control group (P>0.05). The short-term TE of GNCSE rats increased significantly (P<0.05), but in the long term, TE was similar to that in the control group (P>0.05). The expression of pCREB decreased significantly in SE group in comparison with the control group in the short term.

CONCLUSIONEpileptic seizures can lead to learning and memory function impairment in rats, and SE seems to cause greater impact than GNCSE on the learning and memory functions. pCREB might be involved in the pathophysiology of learning and memory deficit in epileptic rats.

Animals ; CREB-Binding Protein ; metabolism ; Hippocampus ; metabolism ; physiopathology ; Kindling, Neurologic ; Maze Learning ; Memory Disorders ; physiopathology ; Pentylenetetrazole ; Rats ; Rats, Sprague-Dawley ; Status Epilepticus ; chemically induced ; metabolism ; physiopathology

PURPOSE: To observe the changes of gait behavior and the expression of wound healing factors of transforming growth factor-β1 (TGF-β1), TGF-β3 and cAMP response element binding protein-1 (CREB-1) during the healing of Achilles tendon in a rat model, and to investigate whether gait analysis can be used to evaluate the tendon healing. METHODS: Achilles tendon of 40 healthy male Sprague-Dawley rats were transected and sutured to establish the Achilles tendon injury (ATI) model. They were randomly divided into 4 groups based on the observational time point at 1, 2, 4 and 6 weeks after injury (n = 10 for each group). Before modeling, 9 rats were randomly selected for CatWalk gait analysis, which contained step cycle, single stance time and average speed. Data were recorded as the normal controls. After then, ATI models were established in the left hind limbs of the all 40 rats (ATI group), while the right hind limbs were only cut and sutured without injury of the Achilles tendon (sham operation group). At 1, 2, 4 and 6 weeks after injury, the gait behavior of the corresponding group of rats (n = 9) as observed and recorded by CatWalk platform. After then, the rats were sacrificed and Achilles tendon of both limbs was harvested. The tendon healing was observed by gross anatomy and histological examination, and the protein and mRNA expression of TGF-β1, TGF-β3, CREB-1 were observed by immunohistochemistry and qPCR. The results of tendon gross grading were analyzed by Wilcoxon rank sum test, and other data were analyzed by one-way analysis of variance among multiple groups. RESULTS: Compared with normal controls, all gait indexes (step cycle, single stance time and average speed) were greatly affected following ATI, which however improved with time. The step cycle was significantly lower at 1, 2 and 4 weeks after ATI (compared with normal controls, all p < 0.05), but almost returned to the normal level at 6 weeks ((0.694 ± 0.102) vs. (0.503 ± 0.094) s, p > 0.05). The single stance time of the ATI group was significantly shorter at 1 and 2 weeks after operation ((0.078 ± 0.010) s at 1 week, (0.078 ± 0.020) s at 2 weeks, all p < 0.001) and revealed no significant difference at 4 weeks (p = 0.120). The average speed of ATI group at 1, 2, 4, 6 weeks was significantly lower than that in the normal control group (all p < 0.001). Gross observation showed that the grade of local scar adhesion in ATI group increased significantly at 2, 4 and 6 weeks, compared with the sham operation group (all p < 0.001). Extensive adhesion was formed at 6 weeks after ATI. The results of HE staining showed that the number of fibroblast increased gradually and arranged more orderly in ATI group at 1, 2 and 4 weeks (all p < 0.001), and decreased at 6 weeks, but it was still significantly higher than that of the sham operation group (p < 0.001). Immunohistochemistry showed that the positive expression of TGF-β1, TGF-β3, CREB-1 in ATI group was higher than that in the sham operation group at 4 time points (all p < 0.05), which reached the peak at 2 weeks after operation and decreased at 4 weeks (p = 0.002, p < 0.001, p = 0.041, respectively). The results of qPCR suggested that the mRNA expression of TGF-β1, TGF-β3, CREB-1 in ATI group was higher than that in the sham operation group at all-time points (all p < 0.05), which reached the peak at 2 weeks after operation, decreased at 4 weeks, and significantly decreased at 6 weeks (all p < 0.001). CONCLUSION Gait behavior indexes are associated with Achilles tendon healing. The study gives an insight of TGF-β1, TGF-β3, CREB-1 changes in the coursing of Achilles tendon healing and these cytokines may be able to be used to regulate the Achilles tendon healing.
Achilles Tendon ; Animals ; CREB-Binding Protein ; Gait Analysis ; Male ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1/genetics* ; Transforming Growth Factor beta3 ; Wound Healing

AIMTo further uncover the possible mechanism of quercetin-mediated inhibitory effect on prostate cancer cells.

METHODSThe cell extracts treated with quercetin or without treatment were used for checking protein expression levels of c-Jun and cAMP response element binding protein (CREB)-binding protein (CBP) by Western blotting assay. Regulatory effects of c-Jun and CBP on the function of androgen receptor (AR) were examined by cotransfection experiment. Finally, a physical interaction of c-Jun and the AR was investigated by coimmunoprecipitation.

RESULTSQuercetin dramatically induced the protein expression of c-Jun which in turn inhibited the AR function. Meanwhile, quercetin had no detectable effect on CBP expression, and the results of transient transfection demonstrated that the ectopic CBP stimulated the transcriptional activity of AR, whereas CBP-mediated stimulation could be attenuated by quercetin. Furthermore, physical interaction of c-Jun and the AR was confirmed by coimmunoprecipitation result.

CONCLUSIONOverexpression of c-Jun induced by quercetin had inhibitory effect on the function of AR protein, and increased CBP expression did not reverse the inhibition by quercetin. Together, quercetin-mediated inhibition on the AR function might be not by competition with limited amount of CBP in the cell, but through a direct association of c-Jun and the AR.

Antineoplastic Agents, Phytogenic ; pharmacology ; CREB-Binding Protein ; genetics ; metabolism ; physiology ; Cell Line, Tumor ; Humans ; Immunoprecipitation ; Male ; Prostatic Neoplasms ; metabolism ; pathology ; Protein Binding ; drug effects ; Proto-Oncogene Proteins c-jun ; genetics ; metabolism ; physiology ; Quercetin ; pharmacology ; Receptors, Androgen ; genetics ; physiology ; Transfection