Biomedical subjects

Maria Gueorguiev

Publications and source records attributed to Maria Gueorguiev.

7 recordsLinked to original sources

PubMed2005

The association of p53 mutations and p53 codon 72, Her 2 codon 655 and MTHFR C677T polymorphisms with breast cancer in Northern Greece.

The aim of this study was to explore a possible association between p53 codon 72, Her 2 codon 655 and MTHFR C677T polymorphisms and breast cancer in Northern Greece. We examined 42 women with breast cancer and 51 controls. A total of 42 women with breast cancer as well as healthy controls were investigated and results showed that p53 codon 72 polymorphism is statistically significantly associated with breast cancer (OR for Arg/Arg to non-Arg/Arg was 6.66, P = 0.0001 at 95% CI 2.63-16.9), but not Her 2 and MTHFR polymorphisms are associated with breast cancer (OR for Ile/Ile to non-Ile/Ile was 1.33, P = 0.54 at 95% CI 0.52-3.38 and OR for T/T versus non-T/T was 1.07, P = 0.89 at 95% CI 0.35-3.25). All subjects were examined for p53 exons 5-8 mutations. Three novel sequence variations in exons 7 and 8 of TP53 gene were found in three patients. One of them induces an amino acid change at Ser 241Gly, the second is a silent mutation Gly244Gly, and the third one results in a premature stop codon 294 (Glu294stop) and a truncated p53 protein.

Adult↗

PubMed2004

Ghrelin--a hormone with multiple functions.

Ghrelin is brain-gut peptide with growth hormone-releasing and appetite-inducing activities. It is mainly secreted from the stomach mucosa but it is also expressed widely in different tissues and therefore may have both endocrine and paracrine effects. Ghrelin is the endogenous ligand of the G protein-coupled growth hormone secretagogue receptor. In the current review we comprehensively summarize (i) the data available regarding the structure, expression pattern and regulation of ghrelin and its receptor; (ii) the available information regarding the effect of ghrelin on the pituitary hormone axis, appetite regulation, cardiac and gastrointestinal function, carbohydrate metabolism, adipose and reproductive tissue, cell proliferation and behavioral effects; (iii) experimental and clinical data regarding circulating ghrelin levels observed in various physiological and pathological conditions; and (iv) data on gene variations of ghrelin and its receptor. It is apparent that ghrelin is involved in many more processes than originally envisaged, and in particular appears to have relatively less relevance to growth hormone physiology and more to the regulation of energy fluxes in the organism. Increasing data link ghrelin to the overall control of energy use and flow in situations where there is a limitation of energy sources and ghrelin appears to play a pivotal role in energy homeostasis.

Animals↗

PubMed2004

Cell cycle dysregulation in pituitary oncogenesis.

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.

Animals↗

PubMed2003

Identification of adrenocorticotropin receptor messenger ribonucleic acid in the human pituitary and its loss of expression in pituitary adenomas.

The ACTH receptor (ACTH-R) is the second member of the melanocortin (MC-2) receptor family that includes five seven-transmembrane G protein-coupled receptors and has been shown to be predominantly expressed in the adrenal cortex. It has been postulated that ACTH may regulate its own secretion through ultra-short-loop feedback within the pituitary. ACTH-secreting adenomas are characterized by resistance to glucocorticoid feedback, and they may have dysregulated ACTH feedback. We therefore investigated the ACTH-R in normal and adenomatous human pituitary tissue. We report here the identification of ACTH-R mRNA in the human pituitary gland, which was confirmed by direct sequencing. We studied the expression of the ACTH-R in 23 normal pituitary specimens and 53 pituitary adenomas (22 ACTH-secreting, nine GH-secreting, eight prolactin-secreting, one TSH-secreting, one FSH-secreting, 10 nonfunctioning, and two silent corticotroph adenomas), using the sensitive technique of real-time quantitative PCR. Contamination of ACTH-secreting adenomas and nonfunctioning pituitary adenomas with nonadenomatous tissue was excluded by lack of Pit-1 expression. ACTH-R mRNA was detected in all normal pituitary specimens, and in situ hybridization colocalized expression to ACTH staining cells only. However, ACTH-R mRNA levels were undetectable in 16 of 22 ACTH-secreting tumors and in both silent corticotroph tumors. Diagnostic preoperative plasma ACTH levels were significantly lower in the ACTH-R positive ACTH-secreting tumors, compared with those who were ACTH-R negative (P = 0.0006). Direct sequencing of the coding region of the ACTH-R in cDNA from three ACTH-secreting tumors positively expressing the receptor showed no mutations, as did sequencing of genomic DNA in three receptor negative ACTH-secreting tumors and the two silent corticotrophs. These results provide further evidence compatible with an ACTH feedback loop in the pituitary and suggest that loss of expression of the ACTH-R in corticotroph adenomas of patients with Cushing's disease may play a role in the resistance to feedback of the pituitary-adrenal axis seen in these patients.

Adenoma↗

PubMed2002

The expression of the F-box protein Skp2 is negatively associated with p27 expression in human pituitary tumors.

The CDK inhibitor p27 plays a pivotal role in controlling cell proliferation during development, and has been implicated in tumorigenesis. Previous studies have demonstrated changes in p27 protein expression, but not in mRNA levels, in human pituitary tumors. It seems probable that the fall in p27 is due to increased degradation through the ubiquitin-proteasome pathway. Skp2 (S-phase kinase-interacting protein) is a specific F-box protein that allows the recognition and binding of phosphorylated p27 to the ubiquitin complex. The aim of our study was thus to investigate the possible role of Skp2 in pituitary tumorigenesis. A total of 59 human pituitary samples, 7 normal and 52 adenomas, were assessed for transcriptional expression of Skp2; 51 pituitary samples were assessed for protein expression. Real-time RT-PCR was performed on cDNA of reverse-transcribed mRNA for relative quantification of the Skp2 transcript. Immunostaining was performed using mouse monoclonal anti-Skp2 antibody. Skp2 mRNA and protein was detectable in every sample studied. Our results showed no significant difference between the pituitary tumors and normal pituitary tissue in Skp2 mRNA or nuclear protein expression. Individual tumor types had similar mRNA expression and variable protein expression. However, samples with high p27 protein expression showed significantly less Skp2 expression than samples with low p27 staining. Our data suggest that increased p27 degradation through the ubiquitin-proteasome pathway could be regulated in pituitary tumors by changes in Skp2 expression, although other factors probably also play a role.

Adenoma↗

PubMed2002

Sequence analysis of the PRKAR1A gene in sporadic somatotroph and other pituitary tumours.

OBJECTIVE: Carney complex (CNC) is an autosomal dominant multiple neoplasia syndrome featuring cardiac, endocrine, cutaneous and neural tumours, as well as a variety of pigmented lesions of the skin and mucosa. Pituitary GH-secreting tumours are found in approximately 10% of patients with CNC. One of the genes responsible for CNC, the PRKAR1A gene located on human chromosome 17q22-24, has recently been cloned. This represents a putative tumour suppressor gene, coding for the type 1alpha regulatory subunit of protein kinase A (PKA), which is found to be mutated in approximately half of the patients with CNC. However, it is currently unclear as to whether similar mutations occur in sporadic pituitary tumours. We have therefore investigated a series of GH-secreting and other pituitary tumours for sequence abnormalities in the PRKAR1A gene. The mRNA produced by the PRKAR1A undergoes decay if it codes for a truncated protein; we therefore also determined PRKAR1A mRNA levels in the tumours, and compared them with known mutant PRKAR1A-carrying lymphocyte samples. METHODS: We extracted RNA from a series of pituitary tumours, reverse transcribed it to cDNA, and directly sequenced the PRKAR1A coding sequence in 17 GH-secreting, three prolactin-secreting, three ACTH-secreting, one FSH-secreting and 10 nonfunctioning pituitary tumours. Lymphocyte and tumour tissue RNA from two patients with CNC was used as positive controls. Using duplex polymerase chain reaction (PCR) with the PRKAR1A and the "housekeeping" gene GAPDH, we determined the relative expression of the PRKAR1A gene in the unknown as well as in the positive control samples. RESULTS AND CONCLUSION: No mutations were found in any of the exons sequenced. Relative mRNA expression was not decreased in any of the sporadic pituitary tumour samples. The present data thus do not suggest a major role for the PRKAR1A tumour suppressor gene in sporadic GH-secreting or other pituitary tumours.

Adenoma↗

PubMed2002

A variation in the ghrelin gene increases weight and decreases insulin secretion in tall, obese children.

Ghrelin is a recently recognized gut-brain peptide originally derived from the gastric mucosa. It stimulates growth hormone release, increases appetite and facilitates fat storage, and may interact with glucose metabolism. We studied the ghrelin gene in a group of 70 tall and obese children (mean age 9.4 year, Z body mass index [BMI] and Z height >3 and/or BMI percentile >99%). We found 10 single nucleotide polymorphisms. One common polymorphism of the ghrelin gene, which corresponds to an amino acid change in the tail of the prepro-ghrelin molecule, was significantly associated with children with a higher BMI (P = 0.001), and with lower insulin secretion during the first part of an oral glucose tolerance test (P = 0.05) although no difference in glucose levels was noted. This might suggest increased insulin sensitivity, although this is not supported by the lack of difference in fasting and 2 hour insulin levels; alternatively, this may be indicative of impaired first phase insulin secretion. These data suggest that variations in the ghrelin gene contribute to obesity in children and may modulate glucose-induced insulin secretion.

Body Height↗