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PubMed2005

Relationship of patients' age to histopathological features of breast tumours in BRCA1 and BRCA2 and mutation-negative breast cancer families.

INTRODUCTION: Our aim was to evaluate the relationship of patients' age to histopathological features of hereditary breast tumours in a series of breast cancer families not selected for age at diagnosis. In sporadic breast cancer, tumours from premenopausal patients have been shown to differ from those of postmenopausal patients, but this phenomenon has been little studied among familial patients. METHODS: Representative areas of all available breast cancer tissue specimens (n = 262) from 25 BRCA1, 20 BRCA2, and 74 non-BRCA1/2 breast cancer families were punched into a tissue microarray. Immunohistochemical staining of oestrogen receptor, progesterone receptor, ERBB2, and p53 as well as the histology and grade of tumours in these three groups of families were studied in different age groups and compared with each other. RESULTS: We found that only breast cancers from young (<50 years) BRCA1+ patients represent features documented as being typical of BRCA1-associated cancers, such as high tumour grade, negativity for oestrogen and progesterone receptors, and overexpression of p53. Among the BRCA2 families, the opposite was found, with a significantly higher frequency of tumours negative for oestrogen and progesterone receptors among the older patients than among the other groups, but no distinctive tumour characteristics among the younger BRCA2 patients. CONCLUSION: Tumours of BRCA1 and BRCA2 carriers aged 50 years or more differed significantly from those of younger carriers. This difference may reflect different biological behaviour and pathways of tumour development among the older and the younger BRCA1 and BRCA2 patients, with impact also on prognosis and survival.

Adult↗
PubMed2005

Derivation of genetic interaction networks from quantitative phenotype data.

We have generalized the derivation of genetic-interaction networks from quantitative phenotype data. Familiar and unfamiliar modes of genetic interaction were identified and defined. A network was derived from agar-invasion phenotypes of mutant yeast. Mutations showed specific modes of genetic interaction with specific biological processes. Mutations formed cliques of significant mutual information in their large-scale patterns of genetic interaction. These local and global interaction patterns reflect the effects of gene perturbations on biological processes and pathways.

Genes, Fungal↗
PubMed2025

Transcriptome sequencing reveals regulatory genes associated with neurogenic hearing loss.

Hearing loss is a prevalent condition with a significant impact on individuals' quality of life. However, comprehensive studies investigating the differential gene expression and regulatory mechanisms associated with hearing loss are lacking, particularly in the context of diverse patient samples. In this study, we integrated data from 10 patients across different regions, age groups, and genders, with their data retrieved from a public transcriptome database, to explore the molecular basis of hearing loss. These samples are mainly from fibroblasts and keratinocytes. Through differential gene expression analysis, we identified key genes, including ICAM1, SLC1A1, and CD24, which have already been shown to play important roles in neurogenic hearing loss. Furthermore, we predicted potential transcriptional regulatory factors that may modulate the expression of these genes. Enrichment analysis revealed biological processes and pathways associated with hearing loss, highlighting the involvement of circadian rhythm disruption and other neuro-related disorders. Although our study is limited by the sample size and the absence of larger-scale investigations, the identified genes and regulatory factors provide valuable insights into the molecular mechanisms underlying hearing loss. Further molecular and cellular experiments are necessary to validate these findings and elucidate the precise regulatory mechanisms involved. In conclusion, our study contributes to the understanding of hearing loss pathogenesis and offers potential targets for molecular diagnostics and gene-based therapies. This provides a foundation for further research into personalized approaches to diagnosing and treating hearing loss.

Humans↗
PubMed1994

Human chorionic gonadotropin beta-subunit nicking enzymes in pregnancy and cancer patient serum.

hCG is a dimer composed of an alpha- and a beta-subunit, joined noncovalently. In addition to the hCG dimer, uncombined alpha- and beta-subunits (free beta) and nicked hCG and free beta molecules (cleaved at 44-45 or 47-48) can be detected in the circulation. Of these circulating molecules, only the intact hCG dimer fully expresses biological activity. The pathways that dissociate, nick, and degrade hCG and beta-subunit molecules in pregnancy are unknown and could have a major role in regulating hormone levels. Immunoassays for intact (nonnicked) hCG and intact (beta-subunit (with < 1% detection of nicked molecules) and a subtractive immunoassay system for measuring nicked hCG levels have been described previously. A multiantibody scavenger assay is described here for measuring nicked beta-subunit levels (< 6% detection of intact beta-subunit). In this report we use these four assays to assess conversion of intact hCG or beta-subunit to nicked forms over time (nicking enzyme activities) in control (healthy nonpregnant), pregnant, and cancer patient serum samples. Pools of pregnancy and control sera were supplemented with intact hCG and its dissociated beta-subunit and incubated at 37 C. Intact and nicked molecule measurements were made between 0-48 h. In two different pools of control sera, no loss of intact hCG or intact beta-subunit and no significant gain in nicked hCG or nicked beta-subunit were detected over 48 h. This indicated a lack of nicking enzyme activity in control serum. In two different pools of first trimester pregnancy sera, we found no obvious loss of intact hCG or gain of nicked hCG levels over 48 h. However, we found 70% and 62% losses (pools 1 and 2) of intact beta-subunit and 51% and 39% gains of nicked beta-subunit over the same time period. We inferred that an uncombined or free beta-subunit-modifying activity was present in pregnancy serum. We repeated the pregnancy serum experiment with six different concentrations of beta-subunit (0.62-29 mg/L). A linear relationship, percent nicking against time, existed for the six concentrations for up to 6 h at 37 C (r = 0.97); after that, the rate of nicking declined. A plot of rate against concentration against revealed a classical Michaelis-Menten enzyme relationship (logarithmic regression, r = 0.96). The pregnancy serum beta-subunit nicking activity was partially purified by gel filtration. A single peak of activity emerged, eluting between the 150,000-443,000 mol wt standards.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed2001

Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade.

A continuing focus of our work has been an effort to understand the signal transduction pathways through which insulin achieves its cellular actions. In the mid-1970s, we and others observed that insulin promoted an increase in Ser/Thr phosphorylation of a subset of cellular proteins. This finding was unanticipated, inasmuch as nearly all of the actions of insulin then known appeared to result from protein dephosphorylation. In fact, nearly 15 years elapsed before any physiologic response to insulin attributable to stimulated (Ser/Thr) phosphorylation was established. Nevertheless, based on the hypothesis that insulin-stimulated Ser/Thr phosphorylation reflected the activation of protein (Ser/Thr) kinases downstream of the insulin receptor, we sought to detect and purify these putative, insulin-responsive protein (Ser/Thr) kinases. Our effort was based on the presumption that an understanding of the mechanism for their activation would provide an entry into the biochemical reactions through which the insulin receptor activated its downstream effectors. To a degree that, in retrospect, is surprising, this goal was accomplished, much in the way originally envisioned. It is now well known that receptor tyrosine kinases (RTKs) recruit a large network of protein (Ser/Thr) kinases to execute their cellular programs. The first of these insulin-activated protein kinase networks to be fully elucidated was the Ras-Raf-mitogen-activated protein kinase (MAPK) cascade. This pathway is a central effector of cellular differentiation in development; moreover, its inappropriate and continuous activation provides a potent promitogenic force and is a very common occurrence in human cancers. Conversely, this pathway contributes minimally, if at all, to insulin's program of metabolic regulation. Nevertheless, the importance of the Ras-MAPK pathway in metazoan biology and human malignancies has impelled us to an ongoing analysis of the functions and regulation of Ras and Raf. This chapter will summarize briefly the way in which work from this and other laboratories on insulin signaling led to the discovery of the mammalian MAP kinase cascade and, in turn, to the identification of unique role of the Raf kinases in RTK activation of this protein (Ser/Thr) kinase cascade. We will then review in more detail current understanding of the biochemical mechanism through which the Ras proto-oncogene, in collaboration with the 14-3-3 protein and other protein kinases, initiates activation of the Raf kinase.

14-3-3 Proteins↗
PubMed2003

TRP channels: formation of signal complex and regulation of cellular functions.

Cellular stimulation from the surrounding extracellular environment via receptors and other pathways evoke activation of Ca(2+)-permeable cation channels. An important clue to understand the molecular mechanisms underlying these receptor-activated cation channels (RACC) was first provided through molecular studies of the transient receptor potential (trp) protein (TRP), which controls light-induced deporlarization in Drosophila photoreceptor cells. Recent studies have revealed that these TRP channels are also activated by diverse stimuli such as heat, osmotic stress, and oxidative stress. Furthermore, involvement of TRP channels has been demonstrated in signaling pathways essential for biological responses, such as proliferation, differentiation, and cell death. These findings encourage usage of TRP channels and their signalplexes as powerful tools for the development of novel pharmaceutical targets.

Animals↗
PubMed2001

Dissecting receptor-mediated Ca2+ influx pathways: TRP channels and their native counterparts.

Cellular stimulation from the surrounding extracellular environment via receptors and other pathways evoke activation of Ca2+-permeable cation channels that form essential signaling pathways in controlling biological responses. An important clue to understand the molecular mechanisms underlying these cation channels (tentatively termed as receptor-mediated cation channels (RMCC)) was first provided through molecular studies of the transient receptor potential (trp) protein (TRP), which controls light-induced depolarization in Drosophila photoreceptor cells. Use of the genetic information and recombinant expression technique lead to the discovery of numerous mammalian TRP homologues revealing novel RMCCs. In this review, we focus on the dramatic progress in the molecular investigation of RMCC in mammalian systems. The recent findings should provide powerful tools for the development of novel pharmaceutical targets.

Animals↗
PubMed2001

Differential gene expression in a DNA double-strand-break repair mutant XRS-5 defective in Ku80: analysis by cDNA microarray.

The ability of cells to rejoin DNA double-strand breaks (DSBs) usually correlates with their radiosensitivity. This correlation has been demonstrated in radiosensitive cells, including the Chinese hamster ovary mutant XRS-5. XRS-5 is defective in a DNA end-binding protein, Ku80, which is a component of a DNA-dependent protein kinase complex used for joining strand breaks. However, Ku80-deficient cells are known to be retarded in cell proliferation and growth as well as other yet to be identified defects. Using custom-made 600-gene cDNA microarray filters, we found differential gene expressions between the wild-type and XRS-5 cells. Defective Ku80 apparently affects the expression of several repair genes, including topoisomerase-I and -IIA, ERCC5, MLH1, and ATM. In contrast, other DNA repair-associated genes, such as GADD45A, EGR1 MDM2 and p53, were not affected. In addition, for large numbers of growth-associated genes, such as cyclins and clks, the growth factors and cytokines were also affected. Down-regulated expression was also found in several categories of seemingly unrelated genes, including apoptosis, angiogenesis, kinase and signaling, phosphatase, stress protein, proto-oncogenes and tumor suppressors, transcription and translation factors. A RT-PCR analysis confirmed that the XRS-5 cells used were defective in Ku80 expression. The diversified groups of genes being affected could mean that Ku80, a multi-functional DNA-binding protein, not only affects DNA repair, but is also involved in transcription regulation. Our data, taken together, indicate that there are specific genes being modulated in Ku80- deficient cells, and that some of the DNA repair pathways and other biological functions are apparently linked, suggesting that a defect in one gene could have global effects on many other processes.

Animals↗
PubMed2006

Repression of secondary metabolite production by exogenous cAMP in Monascus.

The cAMP signal pathway controls various biological functions, including secondary metabolism of filamentous fungi. We found that exogenous cAMP represses the production of lovastatin, red pigments, and citrinin in Monascus. Interestingly, a mutant MK-1 with increased lovastatin and red pigments production was not influenced by cAMP on these productions, indicating that cAMP signaling might be lacking in MK-1.

Cyclic AMP↗
PubMed1996

Anti-tumor promotion with food phytochemicals: a strategy for cancer chemoprevention.

Cancer chemoprevention is currently regarded as a promising avenue for cancer control. In particular, the inhibition of tumor promotion (anti-tumor promotion) in multistage carcinogenesis is expected to be an efficient strategy, because tumor promotion is experimentally accomplished through the long-term, repetitive exposures of rodents to a tumor promoter, and premalignant lesions caused by a tumor promoter regress, at least in their earlier stages. In this review, we first describe the background of cancer chemoprevention studies as well as recent results of clinical trials. Subsequently, some hypothetical biological and cellular pathways in tumor promotion are explored. In addition, the anti-tumor promoting properties of vegetables, fruits, and edible marine algae, together with their active constituents and action mechanisms thus far known, are also described. Anti-tumor promotion with food phytochemicals may be characterized as an efficient and reliable strategy for cancer chemoprevention.

Animals↗
PubMed1999

Why is environmental tobacco smoke more strongly associated with coronary heart disease than expected? A review of potential biases and experimental data.

Despite exposure levels estimated to be equivalent to smoking only 0. 1-1.0 cigarettes per day, exposure to environmental tobacco smoke (ETS) is estimated to increase the risk of death from coronary heart disease (CHD) between 25 and 35% above the risk of nonexposed persons. This surprisingly large risk associated with a seemingly small exposure has raised doubts about the validity of attributing the increased CHD risk to ETS exposure. This paper reviews various biases that have been hypothesized to account for the increased CHD risk associated with ETS in the epidemiologic studies and characterizes the adverse effects of ETS on thrombosis, vascular endothelium, and exercise tolerance observed in experimental studies of humans and laboratory animals. None of the identified factors that has been proposed to introduce a spurious association between ETS and heart disease seem to invalidate the epidemiologic findings, either separately or in combination. In addition, experimental studies of ETS and heart disease demonstrate that acute exposure of humans and other species to ETS affects platelet function, vascular endothelium, and myocardial exercise tolerance at exposure concentrations widely prevalent in the workplace. Because exposure to ETS affects multiple physiologic pathways, it appears biologically plausible that ETS could cause the substantial increase in CHD risk that has been observed in epidemiologic studies.

Animals↗
PubMed1999

Antagonism of the renin-angiotensin-aldosterone system and collagen metabolism in cardiac fibroblasts.

The renin-angiotensin-aldosterone system has emerged as a potential candidate for the accumulation of collagen in cardiac fibroblasts. The traditional renin-angiotensin-aldosterone system can be considered a system in which circulating angiotensin II or aldosterone is delivered to target tissue or cells. However, an independent local renin-angiotensin system has also been described in cardiac cells and evidence has been accumulated for autocrine and/or paracrine pathways by which biological actions of angiotensin II can be mediated. These actions of angiotensin II are primarily mediated through angiotensin II receptors of the subtype I (AT1). When evaluating the effects of angiotensin II in situ, changes in circulating levels and local production both have to be taken into account. Functional angiotensin II receptors have been documented in cardiac fibroblasts although the presence of aldosterone receptors in cardiac fibroblasts is obscure, and the expression of mRNA for mineralocorticoid receptors in cardiac fibroblasts has been described. In vitro, angiotensin II increased cardiac fibroblast-mediated collagen synthesis and mRNA levels of collagen type I, type III, pro-alpha 1 (I) collagen, pro-alpha 1 (III) collagen and fibronectin, and inhibited matrix metalloproteinase I activity. The ability of angiotensin II to induce collagen synthesis and expression of collagen in cardiac fibroblasts may be mediated by an increase in transforming growth factor-beta 1 in an autocrine/paracrine fashion. The angiotensin II-stimulated secretion and expression of collagen was completely abolished by AT1 receptor antagonism, but not affected by AT2 receptor antagonism. The discordant findings that have been reported concerning the in vitro effect of aldosterone on collagen synthesis in cardiac fibroblasts can at least partly be attributed to differences in methodology such as the use of the total population or a sub-population of cardiac fibroblasts. In vivo, chronic infusion of angiotensin II or aldosterone increased the collagen volume fraction in the ventricles. Angiotensin-converting enzyme (ACE) inhibition and AT1 receptor antagonism, but not AT2 receptor antagonism, reduced collagen deposition in the myocardium in spontaneously hypertensive rats. The cardioprotective mechanism of action of ACE inhibitors can be attributed to local blockade of the formation of angiotensin II, to the degradation of bradykinin or to the release of nitric oxide and/or eicosanoids. Angiotensin-converting enzyme inhibitors also reduced collagen deposition in rat myocardium following myocardial infarction suggesting that collagen deposition may in part result from mechanisms other than through AT1 receptors. However, further research is necessary to unravel the various mechanisms involved in the action of angiotensin-converting enzyme inhibitors or of AT1 receptor antagonists on collagen deposition in the myocardium.

Animals↗
PubMed1999

Antagonism of the renin-angiotensin system, hypertrophy and gene expression in cardiac myocytes.

In response to humoral and mechanical stimuli, the myocardium adapts to increased work load through hypertrophy of individual muscle cells. Myocardial hypertrophy is characterized by an increase in cell size in the absence of cell division and is accompanied by changes in gene expression. Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system (RAS), regulates volume and electrolyte homeostasis and is involved in cardiac and vascular growth in rats. In this review, the role of RAS in myocyte protein synthesis (myocyte hypertrophy) and in induction of gene expression will be discussed in rat cardiomyocytes in culture. Traditional RAS can be considered as a system in which circulating Ang II is delivered to target tissues or cells. However, a local RAS has also been described in cardiac cells and evidence has been accumulated for autocrine and/or paracrine pathways by which biological actions of Ang II can be mediated. These actions of Ang II are primarily mediated through Ang II receptors subtype I (AT1-R). When evaluating the effects of Ang II in situ, both changes in circulating levels and local production have to be taken into account. Contrasting results have been found concerning the in vitro effect of Ang II on the protein synthesis in cardiac myocytes and can be at least partly be attributed to methodological problems such as assay of de novo protein synthesis and isolation and separation procedure of cardiac myocytes. The Ang II-induced hypertrophic effect also depends on the existence of nonmyocytes in a cardiocyte culture. In rat cardiocytes, AngII also causes induction of many immediately-early genes (c-fos, c-jun, jun-B, Egr-1 and c-myc) and induces also late markers of cardiac hypertrophy (skeletal alpha-actin and atrial natriuretic peptide expression) and growth factors (TGF-beta 1 gene expression). In vivo AngII via AT1-R, causes not only ventricular hypertrophy but also a shift to the fetal phenotype of the myocardium. Angiotensin-converting enzyme inhibitors and AngII receptor antagonists of the subtype I not only induce the regression but also prevent the development of cardiac hypertrophy in experimental rat models.

Animals↗
PubMed2004

Novel targeted agents in the treatment of lung cancer.

Lung cancer is the leading cause of cancer-related mortality in the US. Although an improvement in outcome is possible with the continued advancement of cytotoxic-based treatment, clinical research is currently focused on utilising novel molecular targets with proven efficacy in preclinical models and a low toxicity profile. This is the result of advances in understanding of tumour biology and molecular pathways that have been implicated in cancer pathogenesis and progression. Novel agents targeting cell cycle regulation, angiogenesis and signal transduction pathways have reached clinical testing in lung cancer and are discussed in this review.

Alkyl and Aryl Transferases↗
PubMed2002

Candidate gene approach for pharmacogenetic studies.

Genetic diversity in the form of single nucleotide DNA polymorphisms (SNPs) contributes to variable disease susceptibility and drug response. The candidate gene approach has been widely used to identify the genetic basis for pharmacogenetic traits and becomes increasingly more powerful with the recent advances in genomic technologies. High-throughput sequencing and SNP genotyping technologies allow the study of thousands of candidate genes and the identification of those involved in drug efficacy and toxicity. Expression-based genomic technologies such as DNA microarrays and proteomics also facilitate the understanding of important biological and pharmacological pathways, thus identifying more candidate genes for SNP studies. Candidate gene-based pharmacogenetic studies will lead to improved drug development, improved clinical trial design and therapeutics tailored to individual genotypes.

DNA, Complementary↗
PubMed2000

Subliminal stimulation research and its implications for psychoanalytic theory and treatment.

As a tribute to Freud's genius, he was able to recognize not only the importance of implicit unconscious learning but also the way it currently impacts on the patient in psychoanalytic therapy. He prevented the patient from viewing the analyst's facial expressions by placing the patient on the couch. In addition, the analyst was instructed not to say too much, to be neutral, nonjudgmental, and calmly reflective. Thus the patient's response to the facial expressions and voice tone of the analyst, even when subliminally perceived, were minimized. This may be even more significant in women, who seem to be more sensitive to nonverbal cues of emotional states. Ferenczi further elaborated on the importance of establishing a connective empathic relationship, using a kindly, soothing voice tone and being emotionally available. Sandler and Sandler (1994) also emphasized the importance of tolerance and acceptance when making interpretations. These clinical instructions diminish external threats to survival and thereby minimize the activation of the amygdala. These procedures in psychoanalytic treatment seem similar to a subliminal MIO message and to the subliminal exposure of a happy face, as mentioned above in the fMRI study by Whalen et al. (1998). The empathic responses of the therapist need to create a condition of safety. In turn, this decreases the patient's vigilance and defensiveness and allows for the emergence of unconscious material that can be worked through verbally and rectified by explicit memory. Another fascinating finding is that Freud (1914) became aware, in his paper on the repetition compulsion, that repressed traumatic and conflictual relationships are acted out behaviorally outside of conscious awareness. He then considered that the focus of analysis should be on analyzing the transference relationship, where this enactment was manifested. Brockman (1998) notes that modern empirical findings confirm Freud's clinical hypotheses regarding the repetition compulsion. Repressed traumatic emotional memories are encoded in the amygdala, and they are unconsciously enacted through behavior, especially in the transference. In summary, childhood and other traumatic memories become encoded in the amygdala and are later enacted and expressed behaviorally, especially in the transference relationship. Working through of the emotional trauma makes these implicit memories explicit and exposes them to adult judgment. When the therapist creates a condition of safety, old memories are reexperienced and detoxified. The memories are experienced as nonthreatening now, thus calming the amygdala and diminishing its activity. Biologically, new neural pathways from the cortex to the amygdala can be established, since the cortex is plastic. This process is slow and may account for the need to repeatedly work through in analysis old conflicted relationships that had threatened security and survival. As imaging techniques improve, we may soon be able to evaluate therapy outcomes scientifically by measuring these actual brain changes. We are on the threshold of establishing a scientific psychoanalysis, as empirical research is providing us with data that integrate the mind and the brain. Subliminal stimulation and brain imaging techniques provide us with important tools for developing an empirical base for psychoanalytic theory and treatment. These techniques were not available to Freud at the turn of the last century, and as we center the new millennium Freud's dream of psychoanalysis having a firm scientific foundation is becoming a reality.

Adult↗
PubMed2002

Psychological outcomes in long-term survivors of childhood leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma: a report from the Childhood Cancer Survivor Study.

OBJECTIVE: To evaluate and compare psychological outcomes in long-term survivors of pediatric leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma and sibling controls. METHODS: Adult survivors of childhood leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma (N = 5736) and sibling controls (N = 2565) were administered a long-term follow-up questionnaire allowing assessment of symptoms associated with depression and somatic distress. RESULTS: The majority of respondents in this study did not demonstrate symptomatology indicative of depression or somatic distress. Survivors, however, were significantly more likely than sibling controls to report symptoms of depression and somatic distress. Women were significantly more likely to indicate symptoms of depression and somatic distress than were men; however, this difference did not vary by survivor/sibling status. Similarly, socioeconomic (SES) variables predicted symptomatic levels of depression and somatic distress for both survivors and siblings, and these effects did not vary by survivor/sibling status. Among leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma survivors, in addition to gender and SES, the only treatment variable that predicted scores indicating depressive symptomatology was exposure to intensive chemotherapy. Exposure to intensive chemotherapy also predicted scores indicative of somatic distress symptoms. No other medical variables, including diagnostic category, age at diagnosis, time since diagnosis, and duration of treatment, predicted symptomatic scores for depression and somatic distress. CONCLUSIONS: This large, sibling-controlled, multisite study of young adult survivors of childhood leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma found that survivors had significant increased risk for reporting symptoms of depression and somatic distress and that intensive chemotherapy added to this risk. However, being a cancer survivor did not compound the effects of gender and SES variables on the 2 outcomes measured. The ability of SES, gender, and treatment-related variables to predict psychological symptoms in this cohort of childhood survivors and sibling controls calls for future research into varied biological and psychosocial pathways by which cancer influences future psychosocial functioning.

Adolescent↗
PubMed2000

Pituitary adenylate cyclase-activating polypeptide acts synergistically with relaxin in modulating ovarian cell function in rats.

The interactive effects of pituitary adenylate cyclase-activating polypeptide (PACAP) and relaxin on the secretion of gelatinases, involved in matrix remodeling, in ovarian theca-interstitial cells and granulosa cells, were investigated in gonadotropin-primed immature rats. The gelatinases secreted from cultured cells were analyzed using gelatin zymography and scanning densitometry. We have previously shown that relaxin stimulated the secretion of a 71 kDa gelatinase, identified as a type IV collagenase (matrix metalloproteinase 2), in rat theca-interstitial cells. This study has demonstrated that PACAP27 and PACAP38, with similar potency, dose-dependently enhanced relaxin-induced secretion of 71 kDa gelatinase, whereas PACAP alone had no effect. In rat granulosa cells, both PACAP27 and PACAP38 alone dose-dependently increased the secretion of a 63 kDa gelatinase. In addition, this study has shown that cAMP signaling pathway mediators act similarly to that of PACAP on gelatinase secretion in rat ovarian cells. Cholera toxin, forskolin and 8-bromoadenosine cAMP augmented relaxin-induced secretion of 71 kDa gelatinase in theca-interstitial cells, and alone they had no effect. These mediators also increased the secretion of 63 kDa gelatinase in granulosa cells. It is well known that the increase in cellular cAMP level is associated with the morphological rounding-up phenomenon in granulosa cells. This study has shown that PACAP and cAMP pathway mediators, but not relaxin, could cause such changes in cell shape in granulosa cells as well as in theca-interstitial cells. In conclusion, this study provides original findings that PACAP acts synergistically with relaxin in stimulating the secretion of gelatinases in rat ovarian theca-interstitial cells and granulosa cells. This supports the idea that relaxin and PACAP may serve as ovarian physiological mediators of gonadotropin function in facilitating the ovulatory process. In addition, PACAP appears to act through the cAMP signaling pathway to affect biological functions in ovarian cells, whereas relaxin does not.

Animals↗