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)

Pituitary adenylate cyclase-activating polypeptides and PAC1-R are expressed during early embryogenesis and PACAP's neurotrophic action supports a role in neuronal development. In the adult brain PACAP functions as a neuroprotective factor that attenuates the neuronal damage resulting from various insults. The tumor suppressor gene p53 and the new zinc finger protein Zac regulate apoptosis and cell cycle arrest through unrelated pathways and both genes are up-regulated under cerebral ischemia. We report here that p53 and Zac induce expression of the PAC1-R gene. By this mechanism p53 and Zac could fine-tune the balance between death promoting and protective signals and may thus fulfil a dual role in ischemia.
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PMID:Induction of the PAC1-R (PACAP-type I receptor) gene by p53 and Zac. 1036 51

The pathogenesis of corticotroph adenomas is unknown. In a recent study accumulation of p53 protein was detected by immunohistochemistry in a substantial proportion of pituitary corticotroph adenomas, and it has been suggested that it may be causally related to their development. However, other immunohistochemical studies have not confirmed the high incidence of p53 accumulation in this tumor type. Therefore, in the present study, p53 protein accumulation was re-examined in a series of 31 cases of corticotroph adenomas, using different sets of well validated anti-p53 antibodies. Furthermore, in view of the known association of p53 protein with apoptosis, and the known property of p53 to form complexes with heat shock proteins (HSPs), the relationship of p53 accumulation in corticotroph adenomas with apoptosis and HSP-70 was also investigated. Tumor samples from 31 patients with Cushing's disease or Nelson's syndrome were studied. Accumulation of p53 protein was tested by the standard ABC method using two different sets of clone Pab1801 and DO-7 monoclonal antibodies, applied after incubation of sections in a microwave oven. Using the DO-7 antibody, nuclear accumulation of p53 protein was detected in a total of 15 cases, with cytoplasmic staining observed in only 3 tumors. In contrast, using the Pab1801 antibody nuclear staining was observed in only 5 adenomas, with 11 adenomas demonstrating focal cytoplasmic immunoreactivity. Parallel sections of all corticotroph tumors demonstrating cytoplasmic accumulation of p53 protein were tested for the immunohistochemical presence of heat shock protein HSP-70. A striking similar distribution pattern of these two proteins was observed. Apoptosis, identified by the in situ end labeling technique, was detected in a total of 15 out of 28 corticotroph adenomas tested. Calculation of the apoptotic labeling index (ALI) by image analysis showed a significantly lower ALI in those corticotroph adenomas demonstrating nuclear p53 accumulation compared to those with no nuclear p53 immunostaining (p < 0.05). There was no significant difference in the ALI between cytoplasmic p53 positive and negative tumors. It is concluded that depending on the antibody used there is a significant variation of p53 protein detection in corticotroph adenomas. Overall, a significant proportion of corticotroph adenomas studied expressed the p53 protein, which depending on the antibody used, was located either in the nucleus and/or the cytoplasm of tumorous corticotroph cells. Cytoplasmic accumulation of p53, as shown by our colocalization studies with HSP-70, may be due to p53/HSP-70 complex formation. Although such a complex-mediated cytoplasmic exclusion of p53 has no significant effect on apoptosis, nuclear accumulation of p53 protein is associated with a significantly lower apoptotic index indicating a failure of p53 protein to exert its apoptotic action in at least a subset of this tumor type.
Pituitary 1999 May
PMID:Immunocytochemical accumulation of p53 in corticotroph adenomas: relationship with heat shock proteins and apoptosis. 1108 Nov 99

160 clinically non-secreting pituitary adenomas were examined in regard to their expression of the markers PCNA, bcl2, Ki 67 in the mib-1 modification and p53 which are still under investigation for their relevance to cell proliferation. The series contained 60 null cell adenomas, 60 oncocytomas and 40 gonadotroph adenomas. The groups that showed a definitely negative and definitely positive staining were evaluated in regard to their further characteristics such as size, invasiveness and recurrence. PCNA showed a highly represented immunostaining index throughout the groups, but not correlation between the PCNA index and an increased recurrence rate could be found. The staining for bcl2 was only rarely positive and only in a small number of cells. No correlation with the clinical data could be seen. We found a significant higher rate of staining in the invasive adenomas in the group of null cell adenomas and oncocytomas for Ki 67, especially in those adenomas expressing p53. p53 positivity was restricted to the invasive adenomas but was found only in 20% of all invasive adenomas. These data confirm in a sufficiently large series of clinically endocrine inactive pituitary adenomas, that p53 and Ki67 immunohistology is useful in evaluating the aggressive behavior of clinically silent pituitary adenomas. Nevertheless, negative results do not exclude clinically relevant invasive behavior.
Pituitary 1999 May
PMID:Proliferation markers in different types of clinically non-secreting pituitary adenomas. 1108 Dec

Pituitary tumors constitute 10% of intracranial neoplasms and are mostly benign, monoclonal adenomas derived from single mutant cells. Pituitary oncogenes have been intensively studied and three of them, gsp, ccnd1, and PTTG are abundant in significant numbers of cases. gsp is present in approximately 40% of Caucasian patients with GH-secreting tumors and results from a mutated, constitutively active alpha subunit of Gs protein. Persistent activation of the cAMP-PKA-CREB pathway may lead to uncontrolled cell proliferation and GH secretion. ccnd1 is overexpressed cyclin D1, and cyclin D1 gene is amplified in some pituitary tumors. PTTG is expressed in most pituitary tumors. PTTG is localized to both the nucleus and cytoplasm and interacts with several protein partners. At least three tumorigenesis mechanisms are proposed for human PTTG. 1) PTTG and FGF form a positive feedback loop and stimulate tumor vascularity. 2) PTTG transactivates c-myc or other pro-proliferation genes. 3) PTTG overexpression causes aneuploidy. PTTG expression activates p53 and causes p53-dependent and -independent apoptosis. Due to lack of functional human pituitary cell cultures and appropriate animal models for pituitary tumors, many of the results reviewed here are obtained from heterologous systems.
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PMID:Oncogene activation in pituitary tumors. 1141 75

Pituitary carcinomas are very rare neoplasms with a poor prognosis. We report a case of Cushing's disease resulting from a pituitary carcinoma in a 22-yr old female, who died of massive hepatic failure. At autopsy, there was invasion of the parasellar structures and vasculature by the tumor, which stained positively only for ACTH. There were two metastatic nodules in the liver, which also stained positively for ACTH. When compared to other cases of Cushing's disease (n = 52), other pituitary adenomas (n = 292). and normal pituitary tissues (n = 21), the pituitary carcinoma was the only one with c-erbB-2 membrane staining in both the sellar-located tissue and liver metastasis. C-erbB-2 staining was present in the cytoplasm of a variable number of cells in 40% of the invasive adenomas (n = 103), while only 1.2% of the noninvasive tumors (n = 241) expressed this protein (p < 0.001). No particular immunohistological type preferentially expressed this protein. In normal pituitary tissues, 10% of the cells expressed cytoplasmic c-erbB-2. A higher index of proliferating cell nuclear antigen (PCNA) in the primary tumor and liver metastasis (10%) was also found compared to other ACTH-secreting adenomas (invasive, 3.4 -t 1 S% vs 1 ii +/- 1.5% in noninvasive) and other pituitary tumors (invasive, 2.9 +/- 1.5% vs 1.5 +/- 1.3% in noninvasive). The PCNA index was significantly higher in invasive tumors than in noninvasive adenomas (p = 0.004). PCNA staining was negative in normal pituitary tissues. Staining for p53, pRB and p(2ras) was negative in the carcinoma and liver metastasis. We suggest that the c-erbB-2 membrane pattern and a higher PCNA index may indicate a worse prognosis in adenohypophyseal neoplasia.
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PMID:Adrenocorticotropin-Producing Pituitary Carcinoma with Expression of c-erbB-2 and High PCNA Index: A Comparative Study with Pituitary Adenomas and Normal Pituitary Tissues. 1211 62

Pituitary carcinomas are only defined by their metastatic growth, which may be intracranial or systemic. To establish further morphological and immunohistochemical differences between pituitary carcinomas and adenomas, 19 ACTH-secreting adenomas (10 non invasive and 9 invasive) and 2 ACTH-secreting carcinomas with their metastases were studied for expression of the intermediate filaments keratin and vimentin and the tumor-associated antigens Ki67, proliferating cell nuclear antigen (PCNA), epidermal growth factor (EGF), cathepsin D, p53, and carcinoembryonic antigen (CEA). Immunohistochemistry was performed using avidin-biotin techniques on formalin-fixed, paraffin-embedded tissue. With the exception of one noninvasive pituitary adenoma, one carcinoma, and the metastases, all tumors contained keratin; none contained vimentin. All tumors stained negative for CEA and p53. Eleven (58.5%) adenomas and both pituitary carcinomas contained Ki67-positive nuclei; 14 (74%) adenomas and one carcinoma revealed PCNA. No correlation was found between the two markers. Seven (38%) adenomas showed a labeling index <1 % for cathepsin D, whereas none of the carcinomas or metastases did so. EGF was found in 7 (38%) adenomas and in both carcinomas. A tendency to a higher rate of EGF positivity in the invasive adenomas was observed. The metastases showed a higher labeling index, and far more intense staining results for Ki67, PCNA, and EGF than the primary tumor. The metastases also had a higher proliferation rate and growth factor content than the carcinoma itself.
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PMID:Proliferation Markers and EGF in ACTH-Secreting Adenomas and Carcinomas of the Pituitary. 1211 89

The cell cycle is the process by which cells grow, replicate their genome and divide. The cell cycle control system is a cyclically-operating biochemical device constructed from a set of interacting proteins that induce and coordinate proper progression through the cycle, and includes cyclins, cyclin-dependent kinases (CDK) and their inhibitors (CDKI). There are mainly two families of CDKI, the INK family (INK4a/p16; INK4b/p15; INK4c/p18 and INK4d/p19) and the WAF/KIP family (WAF1/p21; KIP1/p27; KIP2/p57). Progression through the cell cycle is mainly dependent on fluctuations in the concentration of cyclins and CDKI achieved through the programmed degradation of these proteins by proteolysis within the ubiquitin-proteasome system. There is also a transcriptional regulation of cyclin expression, probably dependent on CDK phosphorylation. The p53 family--p53, p63 and p73--function as transcription factors that play a major role in regulating the response of mammalian cells to stressors and damage, in part through the transcriptional activation of genes involved in cell cycle control (e.g. p21), DNA repair, senescence, angiogenesis and apoptosis. Essential for the maintenance of euploidy during mitosis is human securin, identical to the product of the pituitary tumour-transforming gene (PTTG). Loss of regulation at the G1/S transition appears to be a common event among virtually all types of human tumours. Aberrations of one or more components of the pRb/p16/cyclin D1/CDK4 pathway seem to be a frequent event (80%) in pituitary tumours. The role of p27 is rather that of a haploinsufficient gene. p27-/- mice show an increased growth rate, due to increased cellularity, testicular and ovarian cell hyperplasia and infertility, and hyperplasia of the pituitary intermediate lobe with nearly 100% mortality caused by such a benign pituitary tumour. Although the p27 gene was not found to be mutated in human pituitary tumours and its mRNA expression was similar in tumour samples in comparison with normal pituitaries, the load of p27 protein expression in corticotroph adenomas and pituitary carcinomas was shown to be much lower than those in normal pituitary tissue or other types of pituitary adenoma, suggesting that post-translational processing of p27 accelerates its removal from the nucleus. In respect to p27 degradation and its cellular compartmentalization, several pathways have been explored. Malignant tumours are associated with increased nuclear immunostaining for Jun-activation binding protein-1 (Jab1) which is responsible for phosphorylated p27 export from the nucleus. Corticotrophinomas are characterized by massively increased phosphorylation of p27 on Thr187, but are not associated with changes in Jab1. Macrophage inhibitory factor (MIF), which binds and inactivates Jab1, was noted to be over-expressed in tumours with abundant Jab1, suggesting that it may be part of a compensatory mechanism to moderate Jab1 activity. Proteasomal degradation of p27 requires its ubiquitylation by the SCF ubiquitin ligase, with specific addressing by the F-box protein Skp2 and its co-factor Cks1. Pituitary tumours with high p27 protein expression showed significantly less Skp2 expression than samples with low p27 immunostaining, suggesting that increased Skp2 could play at least a part in this process. No difference was observed in Cks1 mRNA levels between normal pituitaries and pituitary adenomas. The present data suggest that inhibition of growth and tumour development is sensitive not only to the absolute levels of p27 protein, but also to its cellular compartmentalization. Very recent findings from our group have established up-regulation of the serine-threonine kinase Akt in pituitary tumours compared to normal pituitary, which may cause phosphorylation of p27 on Thr157 and cytoplasmic retention of p27. PTTG protein is highly expressed in various human tumours, including pituitary tumours. While its mRNA levels are low in normal pituitary, increases in PTTG transcripts from more than 50% to more than 10-fold were recorded in the majority of a series of pituitary adenomas. Control of the cell cycle is a vital part of the cell's replication machinery. Disruption of this process is commonly seen in pituitary tumours and we are now beginning to identify regulatory elements which are likely to play a major role in pituitary oncogenesis.
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PMID:Cell cycle dysregulation in pituitary oncogenesis. 1528 39

Pituitary carcinomas are rare, making up some 0.2% of all pituitary tumors, but represent a particular challenge to clinical practice. The diagnosis of a pituitary carcinoma requires evidence of metastatic disease, either outside the central nervous system (CNS) or as separate noncontiguous foci within the CNS. They may present as typical pituitary adenomas, which reveal their malignant character only as time progresses, or as peculiarly aggressive tumors ab initio. Recent changes in histopathological classification have clarified many of the features of such tumors, including immunohistochemical staining for Ki-67 and p53, but to date none has been found to be pathognomonic. The majority of carcinomas are secretory, usually arising from corticotroph tumors or prolactinomas, but all histological types and secretory patterns are represented. Treatment is by surgery, transsphenoidal wherever possible, and conventional and stereotactic radiotherapy, but ultimately, a plethora of therapies may be required, including various attempts at medical therapy. Chemotherapy in some instances probably prolongs survival, but, in general, their progress from the diagnosis of carcinomatous changes is progressive and inexorable. However, we do not believe there will be any real prospect of long-term survival until the development and use of therapies targeted at specific molecular abnormalities.
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PMID:Clinical review: Diagnosis and management of pituitary carcinomas. 1574 Dec 48

Pituitary carcinomas are rare neoplasms characterized by craniospinal and/or systemic metastases originated from the pituitary. Their histopathology is frequently indistinguishable from that of benign adenomas. The development of markers that better reflect their behavior is desirable. We present the case of a 47 year-old man with a prolactin-secreting macroadenoma who was submitted to surgeries, cranial radiation therapy, and bromocriptine treatment, but evolved to a fatal outcome after the disclosure of intracranial metastases. Tumor samples underwent p53 and Ki-67 immunohistochemical assessment. p53 was absent in all samples, a rare finding among pituitary carcinomas. Ki-67 proliferative index was 2.80% in the original tumor, 4.40% in the relapse, and 4.45% in the metastasis. The figure in the relapse is higher than the expected for a noninvasive adenoma. In conclusion, p53 staining is not positive in all pituitary carcinomas. A high Ki-67 proliferative index in a pituitary adenoma might indicate a more aggressive behavior.
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PMID:Metastatic prolactinoma: case report with immunohistochemical assessment for p53 and Ki-67 antigens. 1625 73

Pituitary adenomas originating in adenohypophysial cells represent the most common neoplasms of the sella turcica. The pathologist's goal is the optimal diagnosis and classification of pituitary adenomas. Lack of clinicopathological correlations in the past classification of pituitary adenomas, which was based on the tinctorial properties of adenoma cells, limited the importance of histological diagnosis. Morphologic separation of pituitary cells by electron microscopy provided fundamental knowledge to classify pituitary adenomas. Immunohistochemistry represents the gold standard of the current classification. Combined morphologic and immunohistochemical diagnostic approaches resulted in the clinicopathologic classification of pituitary adenomas. The WHO classification of 2004 is based on morphologic features and takes into consideration findings from imaging procedures and clinical symptoms. Morphologic characterization of pituitary tumors and correlation of the hormone product with hormone secretion provides the clinician with useful information. In addition, the utility of tumor markers offers objective information in managing the patient and predicting responses to specific treatment. The Ki-67 labeling index (LI) is widely used for it correlates with invasiveness and probably prognosis. Adenomas showing increased ( >3%) LI and extensive p53 immunoreactivity should be termed "atypical adenomas" suggesting aggressive potential or malignant transformation. Morphologic separation of adenoma from carcinoma is not feasible. The term pituitary carcinoma should be exclusively applied when cerebrospinal and/or systemic metastases are definite.
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PMID:Classification and pathology of pituitary tumors. 1631 7


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