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ABSTRACT: The female internal sex organs develop from the paramesonephric (Mullerian) duct. In male embryos, the regression of the Mullerian duct is caused by the anti-Mullerian hormone (AMH), which plays an important role in the process of testicular descent. The physiological remnant of the Mullerian duct in males is the appendix testis (AT). In our previous study, we presented evidence for the decreased incidence of AT in cryptorchidism with intraoperative surgery. In this report, the expression of the anti-Mullerian hormone receptor type 2 (AMHR2), the specific receptor of AMH, on the AT was investigated in connection with different urological disorders, such as hernia inguinalis, torsion of AT, cysta epididymis, varicocele, hydrocele testis and various forms of undescended testis. The correlation between the age of the patients and the expression of the AMHR2 was also examined. Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry were used to detect the receptor's mRNA and protein levels, respectively. We demonstrate that AMHR2 is expressed in the ATs. Additionally, the presence of this receptor was proven at the mRNA and protein levels. The expression pattern of the receptor correlated with neither the examined urological disorders nor the age of the patients; therefore, the function of the AT remains obscure.Asian Journal of Andrology advance online publication, 7 January 2013; doi:10.1038/aja.2012.135.
Asian Journal of Andrology 01/2013; · 1.52 Impact Factor
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ABSTRACT: The contractile activation of the upper (dome) and lower (base) parts of the urinary bladder show some differences. Cellular mechanisms that might be responsible for cholinergic effects blocking non-adrenergic non-cholinergic contractions in the base of the rat urinary bladder were investigated. Smooth muscle cells were thus freshly isolated or cultured both from the dome and the base of the rat urinary bladder and the contribution from cholinergic and purinergic pathways to their Ca(2+) homeostasis was examined. The expression of nicotinic acetylcholine (nAChR) and P2X2 purinergic receptors on the cultured cells and on tissue sections was investigated. The ATP-evoked Ca(2+) transients in rat smooth muscle cells did not show any desensitization. However, when ATP was administered together with carbamylcholine (CCh), the latter essentially prevented ATP from evoking Ca(2+) transients in smooth muscle cells from the base (suppression to 12 ± 2.5% of control, n = 57; p < 0.01), but not from the dome (99 ± 5% of control, n = 52; p > 0.05) of the rat urinary bladder. While atropine was unable to modify (6 ± 3% of control, n = 14; p < 0.05), α-bungarotoxin (118 ± 12% of control, n = 20; p > 0.05) blocked the inhibitory effects of CCh. Additionally, α7 subunits of nAChR and P2X2 purinergic receptors were identified using immunocytochemistry, immunohistochemistry, and Western blot in cultured urinary bladder smooth muscle cells, in urinary bladder sections, and in urinary bladder muscle strips, respectively, suggesting that the activation of nAChR modifies the action of ATP.
Journal of Muscle Research and Cell Motility 02/2012; 32(6):421-31. · 1.98 Impact Factor
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Noga Gal,
Sofiya Kolusheva,
Noemi Kedei, Andrea Telek,
Taiyabah A Naeem,
Nancy E Lewin,
Langston Lim,
Poonam Mannan,
Susan H Garfield,
Saïd El Kazzouli,
Dina M Sigano,
Victor E Marquez,
Peter M Blumberg,
Raz Jelinek
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ABSTRACT: N-methyl-substituted diacylglycerol-indololactones (DAG-indololactones) are newly synthesized effectors of protein kinase C (PKC) isoforms and exhibit substantial selectivity between RasGRP3 and PKCα. We present a comprehensive analysis of membrane interactions and biological activities of several DAG-indololactones. Translocation and binding activity assays underline significant variations between the PKC translocation characteristics affected by the ligands as compared to their binding activities. In parallel, the fluorescent properties of the ligands were employed for analysis of their membrane association profiles. Specifically, we found that a slight change in the linkage to the indole ring resulted in significant differences in membrane binding and association of the DAG-indololactones with lipid bilayers. Our analysis shows that seemingly small structural modifications of the hydrophobic regions of these biomimetic PKC effectors contribute to pronounced modulation of membrane interactions of the ligands.
ChemBioChem 10/2011; 12(15):2331-40. · 3.94 Impact Factor
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ABSTRACT: Although there are a number of recognized risk factors resulting in cutaneous malignancies, very little is known about the exact mechanism. In keratinocytes different purinergic receptors have been implicated to play essential roles in deciding the fate of the cells through regulating proliferation and differentiation. While P2Y receptors seem to control the former, P2X receptors, among which the P2X(7) receptor is associated with the induction of apoptosis, are likely to be responsible for the latter. Forty mJ/cm(2) UV-B irradiation decreased the number of viable cells as assessed using MTT assay. This irradiation decreased the amount of both P2X(1) and P2Y(2) receptors and essentially destroyed the P2X(7) receptors in surviving cells. Morphology of ATP-induced Ca(2+) transients were altered in irradiated cells compared to control. The amplitude and the rate of rise of the transients were decreased and the return to resting [Ca(2+)](i) prolonged. This observation is consistent with the finding that in control cells mostly ionotropic, while in irradiated cells mostly metabotropic receptors were underlying the response to ATP. These alterations in the expression pattern of purinergic receptors and in the Ca(2+) transients could explain the observed decreased tendency for ATP-induced apoptosis and possibly contribute to the malignant transformation of keratinocytes.
Journal of photochemistry and photobiology. B, Biology 08/2011; 105(1):113-8. · 1.87 Impact Factor
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Noemi Kedei,
Emanuel Lubart,
Nancy E Lewin, Andrea Telek,
Langston Lim,
Poonam Mannan,
Susan H Garfield,
Matthew B Kraft,
Gary E Keck,
Sofiya Kolusheva,
Raz Jelinek,
Peter M Blumberg
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ABSTRACT: Phorbol 12-myristate 13-acetate (PMA) and bryostatin 1 are both potent protein kinase C (PKC) activators. In LNCaP human prostate cancer cells, PMA induces tumor necrosis factor alpha (TNFα) secretion and inhibits proliferation; bryostatin 1 does not, and indeed blocks the response to PMA. This difference has been attributed to bryostatin 1 not localizing PKCδ to the plasma membrane. Since phorbol ester lipophilicity influences PKCδ localization, we have examined in LNCaP cells a series of phorbol esters and related derivatives spanning some eight logs in lipophilicity (logP) to see if any behave like bryostatin 1. The compounds showed marked differences in their effects on proliferation and TNFα secretion. For example, maximal responses for TNFα secretion relative to PMA ranged from 97 % for octyl-indolactam V to 24 % for phorbol 12,13-dibenzoate. Dose-response curves ranged from monophasic for indolactam V to markedly biphasic for sapintoxin D. The divergent patterns of response, however, correlated neither to lipophilicity, to plasma membrane translocation of PKCδ, nor to the ability to interact with model membranes. In U937 human leukemia cells, a second system in which PMA and bryostatin 1 have divergent effects, viz. PMA but not bryostatin 1 inhibits proliferation and induces attachment, all the compounds acted like PMA for proliferation, but several induced a reduced level or a biphasic dose-response curve for attachment. We conclude that active phorbol esters are not all equivalent. Depending on the system, some might partially resemble bryostatin 1 in their behavior; this encourages the concept that bryostatin-like behavior may be obtained from other structural templates.
ChemBioChem 05/2011; 12(8):1242-51. · 3.94 Impact Factor
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Lívia Kosztka,
Zoltán Rusznák,
Dénes Nagy,
Zsuzsanna Nagy,
János Fodor,
Géza Szucs, Andrea Telek,
Mónika Gönczi,
Olga Ruzsnavszky,
Norbert Szentandrássy,
László Csernoch
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ABSTRACT: TASK-3 channel overexpression was shown to facilitate the survival of malignantly transformed cells, possibly by providing greater hypoxia tolerance through a still unknown mechanism. Although it has been suggested previously that TASK-3 channels are expressed in the mitochondrial membranes, their role here remains elusive. In this study, a transient transfection of TASK-3 knockdown melanoma cell cultures was produced to show the significance of TASK-3 expression. Reduction of the TASK-3 protein biosynthesis induced characteristic changes in cell morphology, reduced the amount of DNA and decreased metabolic activity and mitochondrial function of melanoma cells when compared with control. These findings indicate that TASK-3 channel expression and function is indispensable for the proliferation and/or survival of the melanoma cells, as they seem to contribute to their mitochondrial functions. The significance is that, in this study, we have shown that TASK-3 channels are expressed in the mitochondria of melanoma malignum cells, and they are essential for maintaining cellular integrity and viability. The TASK-3 knockdown melanoma cell line had altered morphology, reduced DNA content, decreased metabolic activity and impaired mitochondrial function. These data indicate that TASK-3 channels are functionally present in the mitochondria of the melanoma cells, and their function is essential for the survival of these cells, thus TASK-3 channels may be the possible targets of future anticancer therapy.
Melanoma research 04/2011; 21(4):308-22. · 2.06 Impact Factor
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Noemi Kedei, Andrea Telek,
Alexandra Czap,
Emanuel S Lubart,
Gabriella Czifra,
Dazhi Yang,
Jinqiu Chen,
Tyler Morrison,
Paul K Goldsmith,
Langston Lim,
Poonam Mannan,
Susan H Garfield,
Matthew B Kraft,
Wei Li,
Gary E Keck,
Peter M Blumberg
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ABSTRACT: Bryostatin 1 has attracted considerable attention both as a cancer chemotherapeutic agent and for its unique activity. Although it functions, like phorbol esters, as a potent protein kinase C (PKC) activator, it paradoxically antagonizes many phorbol ester responses in cells. Because of its complex structure, little is known of its structure-function relations. Merle 23 is a synthetic derivative, differing from bryostatin 1 at only four positions. However, in U-937 human leukemia cells, Merle 23 behaves like a phorbol ester and not like bryostatin 1. Here, we characterize the behavior of Merle 23 in the human prostate cancer cell line LNCaP. In this system, bryostatin 1 and phorbol ester have contrasting activities, with the phorbol ester but not bryostatin 1 blocking cell proliferation or tumor necrosis factor alpha secretion, among other responses. We show that Merle 23 displays a highly complex pattern of activity in this system. Depending on the specific biological response or mechanistic change, it was bryostatin-like, phorbol ester-like, intermediate in its behavior, or more effective than either. The pattern of response, moreover, varied depending on the conditions. We conclude that the newly emerging bryostatin derivatives such as Merle 23 provide powerful tools to dissect subsets of bryostatin mechanism and response.
Biochemical pharmacology 03/2011; 81(11):1296-308. · 4.25 Impact Factor
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ABSTRACT: Protein kinase C (PKC) represents the most prominent of the families of signaling proteins integrating response to the ubiquitous
lipophilic second messenger sn-1,2-diacylglycerol and to its ultrapotent analogs, the tumor-promoting phorbol esters. Response
is mediated through twin conserved zinc finger structures, the C1 domains. The C1 domains function as hydrophobic switches,
for which ligand binding completes a hydrophobic surface on the face of the C1 domain, driving membrane association of PKC
and enzymatic activation. Since the lipid bilayer provides critical contacts for ligand binding, along with the C1 domain,
membrane heterogeneity provides an important mechanism for diversity, as do the differential functions of the twin C1 domains.
Consistent with such mechanistic diversity, PKC ligands can differ dramatically in biological consequences. Thus, whereas
PKC ligands have provided the paradigm for tumor promoters, some PKC ligands in fact function as inhibitors of tumor promotion.
Reflecting the central role of PKC in cellular signaling, PKC has emerged as a promising therapeutic target for cancer with
several PKC ligands currently in clinical trials.
KeywordsC1 domain-Diacylglycerol-Phorbol ester-Protein kinase C
12/2009: pages 25-53;
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ABSTRACT: The purpose of this study was to investigate the effects of an elevated hydrostatic pressure of hydrocele on the structural integrity and steroid receptor expression pattern of the appendix testis in children. Twenty-six testicular appendages were obtained from boys (aged between 13 and 79 months, mean 40 months) who underwent surgical exploration because of hydrocele or congenital inguinal hernia. The tissue sections of testicular appendages were stained with hematoxylin-eosin. Immunohistochemistry and immunofluorescence laser microscopy were performed using monoclonal mouse anti-human receptors against androgen and estrogen receptors. Patients were divided into three groups: group A (n = 8) represented patients with groin hernia without hydrocele, who served as control group; group B (n = 7) represented patients with communicating hydrocele; and group C (n = 11) represented patients with noncommunicating hydrocele. The tissue sections of appendix testis expressed both androgen and estrogen receptors in all patients in groups A and B, and epithelial destruction was not present. The presence of androgen receptor (two of 11, P < 0.001) and estrogen receptor (four of 11, P = 0.006) was lower and the number of appendix testes with epithelial destruction was higher (eight of 11, P = 0.001) in group C. We demonstrated that groin hernia and communicating hydrocele did not influence the receptor expression pattern and the anatomic structure of testicular appendages, whereas noncommunicating hydrocele caused damage as indicated by the absence of steroid receptors and destruction of the epithelial surface. A better understanding of the physiological role of testicular appendages may change the indications of surgical treatment in patients with noncommunicating hydrocele.
Asian Journal of Andrology 09/2009; 11(6):741-5. · 1.52 Impact Factor
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Maria J Comin,
Gabriella Czifra,
Noemi Kedei, Andrea Telek,
Nancy E Lewin,
Sofiya Kolusheva,
Julia F Velasquez,
Ryan Kobylarz,
Raz Jelinek,
Peter M Blumberg,
Victor E Marquez
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ABSTRACT: Diacylglycerol lactones built with a rigid 4-[(methylphenyl)ethynyl]phenyl rod that is separated from the exocyclic acylcarbonyl of the DAG-lactone core by a spacer unit of variable length were synthesized and studied. Binding affinities for a panel of classical and novel PKC isozymes in two different phospholipid environments, one corresponding to the plasma membrane of cells, were determined. The kinetics and site of translocation for the PKC isozymes alpha and delta upon treatment with the compounds were also studied as well as the early response of ERK phosphorylation and the late response of induction of apoptosis in the human prostatic carcinoma cell line LNCaP. Finally, the compounds were evaluated in terms of their interaction with biomimetic lipid/polydiacetylene membranes by the associated chromatic response. The different spatial disposition of the rigid structural motif on the DAG-lactones contributes to differential activity.
Journal of Medicinal Chemistry 05/2009; 52(10):3274-83. · 4.80 Impact Factor
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ABSTRACT: Both changes in intracellular calcium concentration ([Ca(2+)](i)) and activation of certain protein kinase C (PKC) isoforms play a crucial role in keratinocyte functions. To better understand the interaction between these two signalling pathways we investigated the resting [Ca(2+)](i) and the extracellular ATP-induced changes in [Ca(2+)](i) on HaCaT cell clones overexpressing either the classical alpha or the beta PKC isoform. These PKC isoenzymes were previously shown to decrease (alpha) or increase (beta) cell proliferation and augment (alpha) or suppress (beta) cell differentiation. Keratinocyte clones with decreased proliferation rate were found to have unaltered resting [Ca(2+)](i), but responded with greater calcium transients to the application of 180 mum of ATP. In contrast, clones with increased proliferation rate had elevated resting [Ca(2+)](i) and suppressed calcium responses to ATP. Calcium transients on PKCbeta clones displayed a faster falling phase. Each clone had a distinct purinergic receptor expression pattern, some of which paralleled the altered proliferation rate and calcium handling. Keratinocytes overexpressing PKCbeta revealed decreased P2X1 and increased P2Y1 receptor expression as compared with the control or PKCalpha clones. The expression level of P2X7 was significantly increased in keratinocytes overexpressing PKCalpha. On the other hand neither the P2X2 nor the P2Y2 expression was altered significantly in the cell types investigated. These data indicate that a modified proliferation and differentiation pattern is associated with altered calcium handling in keratinocytes. The observations also suggest that different PKC isoenzymes have different effects on the phosphatidyl-inositol signalling pathway.
Experimental Dermatology 08/2008; 17(7):584-91. · 3.54 Impact Factor
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ABSTRACT: The presence of TASK-3 channels has been described in a number of healthy and malignantly transformed cells, showing mainly intracellular distribution with relatively insignificant labelling of the cell surface membrane. In this work, immunochemical and molecular biology methods were utilised to establish the intracellular organelle whose TASK-3 expression accounts for this strong intracellular labelling using cultured melanoma and HaCaT cells. Before the immunocytochemical experiments, the presence of TASK-3 mRNA was also confirmed in melanoma cells. Comparison of the results of the TASK-3- and mitochondrion-specific labelling indicated that the TASK-3 channel subunits were strongly expressed by mitochondria in both investigated cell types. Moreover, prominent TASK-3 expression of keratinocytes could also be demonstrated in histological sections excised from the human skin. These results indicate that TASK-3 channels are present in the mitochondria in both malignantly transformed and healthy cells, suggesting that they might have roles in ensuring mitochondrial functions.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 05/2008; 452(4):415-26. · 2.49 Impact Factor
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ABSTRACT: The incidence of appendix testis has been shown to be 76% in descended and 24% in undescended testis in our previous intraoperative survey. To determine the possible role of the appendix testis in the process of testicular migration, we compared the androgen and estrogen receptor status of appendix testis in descended and undescended testes.
Thirty-seven appendix testes were collected intraoperatively and the expression of androgen and estrogen receptors were examined with immunostaining and immunofluorescence labeling. Based on the diagnosis, the specimens were divided into three groups. Group H (groin hernia, n = 11, as a group of descended testis), Group AU (acquired undescended testis, n = 14), and Group CU (congenital undescended testis, n = 12).
The testicular appendages were found to express both androgen and estrogen receptors in Group H and Group AU, but specimens in Group CU were only estrogen receptor positive, whereas androgen receptors were not present.
The presence of the androgen receptor in the appendix testis of the descended testes and acquired undescended testes and its absence in patients with congenital undescended testis suggests that the appendix testis might play a role in the process of testicular descent.
International Journal of Urology 03/2008; 15(2):171-4. · 1.75 Impact Factor
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ABSTRACT: Recent studies strongly suggest that the cannabinoid system is a key player in cell growth control. Since the organ-culture of human hair follicles (HF) offers an excellent, clinically relevant model for complex tissue interaction systems, we have asked whether the cannabinoid system plays a role in hair growth control. Here, we show that human scalp HF, intriguingly, are both targets and sources of endocannabinoids. Namely, the endocannabinoid N-arachidonoylethanolamide (anandamide, AEA) as well as the exocannabinnoid delta (9) -tetrahydrocannabinol dose-dependently inhibited hair shaft elongation and the proliferation of hair matrix keratinocytes, and induced intraepithelial apoptosis and premature HF regression (catagen). These effects were inhibited by a selective antagonist of cannabinoid receptor-1 (CB1). In contrast to CB2, CB1 was expressed in a hair cycle-dependent manner in the human HF epithelium. Since we successfully identified the presence of endocannabinoids in human HF, our data strongly suggest that human HF exploit a CB1-mediated endocannabinoid signaling system for negatively regulating their own growth. Clinically, CB1 agonists may therefore help to manage unwanted hair growth, while CB1 antagonists might counteract hair loss. Finally, human HF organ culture offers an instructive, physiologically relevant new research tool for dissecting "nonclassical" effects of endocannabinoids and their receptor-mediated signaling in general.
The FASEB Journal 12/2007; 21(13):3534-41. · 5.71 Impact Factor
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ABSTRACT: Keratinocyte proliferation and differentiation is strongly influenced by mechanical forces. We investigated the effect of osmotic changes in the development of HaCaT cells in culture using intracellular calcium measurements, electrophysiological recordings and molecular biology techniques. The application of hypotonic stress (174 mOsmol/l) caused a sustained hyperpolarization of HaCaT cells from a resting potential of -27 +/- 4 to -51 +/- 9 mV. This change was partially reversible. The surface membrane channels involved in the hyperpolarization were identified as chloride channels due to the lack of response in the absence of the anion. Cells responded with an elevation of intracellular calcium concentration to hypotonic stress, which critically depended on external calcium. The presence of phorbol-12-myristate-13-acetate in the culture medium for 12 h augmented the subsequent response to hypotonic stress. A sudden switch from iso- to hypotonic solution increased cell proliferation and suppressed the production of involucrin, filaggrin and transglutaminase, markers of keratinocyte differentiation. It is concluded that sudden mechanical forces increase the proliferation of keratinocytes through alterations in their membrane potential and intracellular calcium concentration. These changes together with additional modifications in channel expression and intracellular signalling mechanisms could underlie the increased proliferation of keratinocytes in hyperproliferative skin diseases.
Experimental Dermatology 05/2007; 16(4):302-10. · 3.54 Impact Factor
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Journal of Investigative Dermatology 09/2006; 126(8):1909-12. · 6.31 Impact Factor
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Eniko Bodó,
Tamás Bíró, Andrea Telek,
Gabriella Czifra,
Zoltán Griger,
Balázs I Tóth,
Alessandra Mescalchin,
Taisuke Ito,
Albrecht Bettermann,
László Kovács,
Ralf Paus
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ABSTRACT: The vanilloid receptor-1 (VR1, or transient receptor potential vanilloid-1 receptor, TRPV1) is activated by capsaicin, the key ingredient of hot peppers. TRPV1 was originally described on sensory neurons as a central integrator of various nociceptive stimuli. However, several human skin cell populations are also now recognized to express TRPV1, but with unknown function. Exploiting the human hair follicle (HF) as a prototypic epithelial-mesenchymal interaction system, we have characterized the HF expression of TRPV1 in situ and have examined TRPV1 signaling in organ-cultured human scalp HF and outer root sheath (ORS) keratinocytes in vitro. TRPV1 immunoreactivity was confined to distinct epithelial compartments of the human HF, mainly to the ORS and hair matrix. In organ culture, TRPV1 activation by capsaicin resulted in a dose-dependent and TRPV1-specific inhibition of hair shaft elongation, suppression of proliferation, induction of apoptosis, premature HF regression (catagen), and up-regulation of intrafollicular transforming growth factor-beta(2). Cultured human ORS keratinocytes also expressed functional TRPV1, whose stimulation inhibited proliferation, induced apoptosis, elevated intracellular calcium concentration, up-regulated known endogenous hair growth inhibitors (interleukin-1beta, transforming growth factor-beta(2)), and down-regulated known hair growth promoters (hepatocyte growth factor, insulin-like growth factor-I, stem cell factor). These findings strongly support TRPV1 as a significant novel player in human hair growth control, underscore the physiological importance of TRPV1 in human skin beyond nociception, and identify TRPV1 as a promising, novel target for pharmacological manipulations of epithelial growth disorders.
American Journal Of Pathology 05/2005; 166(4):985-98. · 4.89 Impact Factor
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Journal of Investigative Dermatology 09/2004; 123(2):410-3. · 6.31 Impact Factor
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Journal of Investigative Dermatology 07/2004; 123(2):410-413. · 6.31 Impact Factor
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ABSTRACT: Kísérleteinkben az egyik központi intracelluláris jelátviteli molekulacsalád, a protein kináz C (PKC) rendszer izoenzimjeinek a sejtnövekedés, valamint a kapcsolódó biológiai folyamatok szabályozásában betöltött szerepét vizsgáltuk. Humán és emlős vázizomsejteket, valamint a humán bőrből és a bőrfüggelékekből származó különféle sejttípusokat (pl. keratinocyták, sebocyták, szőrtüsző) vizsgálva megállapítottuk, hogy a sejtek jellegzetes és az adott sejttípus proliferációs és differenciátsági állapotától függő PKC izoenzimmintázattal rendelkeznek. Kombinált farmakológiai, sejtélettani, valamint molekuláris biológiai megközelítést alkalmazva kimutattuk azt is, hogy a különféle PKC izoformák specifikus, egymással gyakran ellentétes, ugyanakkor az adott sejt típusától igen jelentős mértékben függő módon képesek az in vitro és in vivo sejtproliferáció, a differenciálódás, a tumorgenezis, a mediátortermelés, valamint a receptor-mediált jelátvitel folyamatainak szabályozására. | In our experiments, we have investigated the involvement of one of key intracellular signaling molecule family, i.e. the isoenzymes of the protein kinase C (PKC) system, in the regulation of cellular growth and related biological processes. On human and mammalian skeletal muscle cells as well as on various cell types derived from the human skin and its appendages (e.g. keratinocytes, sebocytes, hair follicles) we have shown that the cells possess characteristic PKC isoform patterns which strongly depend on the actual proliferation and differentiation status on the given cell type. Using combined techniques of pharmacology, cellular physiology, and molecular biology we have furthermore presented that the different PKC isoenzymes play specific yet differential, often antagonistic, and cell type-dependent roles in the regulation of in vitro and in vivo cellular proliferation, differentiation, tumorigenesis, mediator production, and receptor-coupled cellular signaling mechanisms.
