S Horibe

Evidence for coupling of phosphotyrosine phosphatase to gonadotropin-releasing hormone receptor in ovarian carcinoma membrane

Gonadotropin‐releasing hormone (Gn‐RH) receptor (Gn‐RHR) has been demonstrated in epithelial ovarian carcinoma (Imai et al., Cancer 1994;74:2555‐61). To examine whether Gn‐RHR mediates direct antiproliferative effects, we attempted to determine stimulatory regulation by Gn‐RH of phosphotyrosine phosphatase (PTP) activity in plasma membranes isolated from ovarian carcinoma samples.

Gi protein activation of gonadotropin-releasing hormone–mediated protein dephosphorylation in human endometrial carcinoma

OBJECTIVE Gonadotropin-releasing hormone receptor is demonstrated in uterine endometrial carcinomas. This study was performed to determine gonadotropin-releasing hormone receptor-mediated membrane events and to identify the guanosine triphosphate binding protein (G protein) subtypes linked to gonadotropin-releasing hormone receptor in the tumors. STUDY DESIGN Endometrial carcinomas surgically removed had been screened for gonadotropin-releasing hormone receptor expression before plasma membrane isolation. The phosphoprotein level was observed in the phosphorus 32-labeled incorporation from [gamma-32P]adenosine triphosphate into the isolated plasma membranes. The Gi (alpha subunit) protein was detected by immunoblotting and pertussis toxin-catalyzed adenosine diphosphate ribosylation. RESULTS Incubation of phosphorus 32-labeled membranes with a gonadotropin-releasing hormone analog in the presence of guanosine thiotriphosphate caused a remarkable loss of phosphoprotein from 35 kd protein. This dephosphorylation action was dose dependent of the gonadotropin-releasing hormone analog, and the maximal effect (90% loss) occurred at 100 nmol/L. Pertussis toxin brought about adenosine diphosphate ribosylation of an immunodetected G alpha i. Gonadotropin-releasing hormone analog alone or guanosine thiotriphosphate alone had no effect. Pretreatment of the membrane with the pertussis toxin completely inhibited gonadotropin-releasing hormone-mediated dephosphorylation of the 35 kd protein. CONCLUSION These data demonstrate the coupling of gonadotropin-releasing hormone receptor to protein dephosphorylation through Gi, raising the possibility that the antimitogenic action of gonadotropin-releasing hormone may occur by release of the action of protein phosphorylation to promote cell growth.

Frequent expression of Fas in gonadotropin-releasing hormone receptor-bearing tumors

OBJECTIVE Fas, a cell surface receptor, mediates cell death by means of apoptosis in a variety of cell types. Gonadotropin-releasing hormone (GnRH) receptor-bearing tumors undergo the apoptosis with GnRH analogs. The authors attempted to determine the frequency with which Fas is present in the GnRH receptor-bearing tumors. STUDY DESIGN Surgically removed gynecological tumors were screened for GnRH receptor expression prior to analyses. Fas was characterized by immunoblotting of membrane proteins with the specific antibodies. Fas messenger ribonucleic acid (mRNA) was determined by reverse transcription-polymerase chain reaction using oligonucleotide primers synthesized according to the published Fas sequence. RESULTS Immunoreactive Fas and Fas mRNA were detected in a high proportion (94.4%) of the specimens from endometrial carcinomas (8 of 9), ovarian carcinomas (7 of 7), and uterine leiomyosarcomas (2 of 2); all these expressed GnRH receptor. There was neither substantial Fas nor GnRH receptor in 9 cervical carcinomas. Cloned cell lines gave identical results to those obtained in their respective mother tumors. CONCLUSION These data might suggest the frequent expression of Fas in the GnRH receptor-bearing tumors, but not in the GnRH receptor-negative tumors. Despite a poorly understood processes of apoptosis at present, there may be at least some similarity in signal transduction pathway utilized by GnRH analogs and Fas ligands.

Drastic elevation of serum CA125, CA72-4 and CA19-9 levels during menses in a patient with probable endometriosis

Levels of CA125, CA72-4 and CA19-9, serum markers for ovarian cancer, were measured throughout menstrual cycles in a patient with probable pelvic endometriosis. The patient had CA125 levels >1000 U ml(-1), CA72-4>10 U ml(-1) and CA19-9>150 U ml(-1) during but not after menses (P<0.01). In luteal phase and premenstrual phase, the levels of these markers seemed to return normal ranges, although CA125 remained over the upper normal limit. Knowledge that a physiological elevation of these markers may occur during menses might avoid misinterpretation.

Detection of SRY in 45,X/47,XYY mosaicism leading to phenotypic female

SRY on the Y chromosome initiates male sex determination. We tested a phenotypic female with sex chromosome mosaicism, X/XYY, for SRY expression. SRY was determined by polymerase chain reaction (PCR) amplification in genomic DNA from a female patient with a sex chromosome mosaic complement, 45, X/47, XYY, followed by sequencing analyses. The patient yielded the PCR product with predicted size and homology to the consensus sequence of SRY. The demonstration of SRY provides evidence that the female phenotype in the presence of sex chromosome mosaicism, X/XYY, may result from alterations in another part of the sex‐determining pathway or downstream from SRY.

A gonadotropin-releasing hormone analogue impairs glucose tolerance in a diabetic patient.

Changes in serum glucose levels were examined in a female with insulin-independent diabetes who received a gonadotropin-releasing hormone (GnRH) analog treatment for pelvic endometriosis. The mean blood glucose levels were higher on busereline therapy, and higher levels of hemoglobin A1c were noted on busereline therapy (range 6.9-12.5%) versus pre- and post-treatment (range 5.1-5.9%). Hormonal alteration induced by GnRH analog treatment may impair glucose tolerance.

Phosphotyrosine Phosphatase Activity in Ovarian Carcinoma Cells

A number of cellular processes, including cell proliferation and differentiation, appear to be regulated by the phosphorylation of proteins on tyrosine residues (1,2). The level of tyrosine phosphorylation of intracellular protein substrates is determined by the balance of phosphorylation by tyrosine kinase and dephosphorylation by phosphotyrosine phosphatase (PTPase) activities. Recent studies have proposed a role for PTPase in counterbalancing the growth-promoting effects of tyrosine kinases (3-5). Because the enzymatic activity of PTPases far exceeds that of tyrosine kinases (6-8), the PTPases may play an important physiological role in regulating growth, differentiation and neoplastic transformation.