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1.  INSL3/RXFP2 Signaling in Testicular Descent: Mice and Men 
Mutations of the insulin-like 3 (INSL3) hormone or its receptor RXFP2 cause intraabdominal cryptorchidism in male mice. Specific RXFP2 expression in mouse gubernacula was detected at embryonic day 14.5 (E14.5) and markedly increased after birth in the developing cremaster muscle, as well as in the epididymis, testicular Leydig and germ cells. INSL3 treatment stimulated cell proliferation of embryonic gubernacular and Leydig cells implicating active INSL3-mediated signaling. The transcription factor SOX9, a known male sex determination factor, up-regulated the activity of the RXFP2 promoter. INSL3 is sufficient to direct the first transabdominal phase of testicular descent in the absence of hypothalamic-pituitary-gonadal axis signaling or Hoxa10 but their presence is important for inguinoscrotal testicular descent. Similarly, conditional ablation of the androgen receptor gene in gubernacular cells resulted in disruption of inguinoscrotal descent. We performed mutation screening of INSL3 and RXFP2 in human patients with cryptorchidism and control subjects from different populations in Europe and USA. Several missense mutations were described in both the INSL3 and RXFP2 genes. A novel V39G INSL3 mutation in a patient with cryptorchidism was identified, however the functional analysis of the mutant peptide did not reveal compromised function. In more than 2000 patients and controls analyzed to date the T222P RXFP2 mutation is the only one strongly associated with the mutant phenotype. The T222P mutant receptor transfected into 293T cells had severely decreased cell membrane expression, providing the basis for the functional deficiency of this mutation.
PMCID: PMC2970567  PMID: 19416188
testis; cryptorchidism; INSL3; RXFP2; hormones
2.  Relaxin Signaling in Uterine Fibroids 
Uterine fibroid is the most common tumor of female reproductive organs. The role of relaxin signaling in leiomyoma development was analyzed. We used 23 matched pairs of leiomyoma and normal myometrium samples to compare the expression of relaxin family peptide receptors RXFP1, RXFP2, caveolin 1, desmin, steroid receptors and their co-factors NCOR1 and NCOR2. The expression of RXFP1 evaluated by quantitative RT-PCR was down-regulated in fibroid tissues. Relaxin or INSL3 treatment suppressed TGF-╬▓ induced phosphorylation of SMAD2 in rat leiomyoma ELT-3 cells in vitro suggesting a possible involvement of relaxins in etiology of leiomyoma.
PMCID: PMC2954601  PMID: 19416222
leiomyoma; transforming growth factor; relaxin; INSL3; phospho-SMAD2
3.  Relaxin/RXFP1 Signaling in Prostate Cancer Progression 
We have shown that relaxin peptide expression was significantly elevated in recurrent human prostate cancer. Stimulation with relaxin increased migration, invasiveness, proliferation, and adhesion of LNCaP and PC3 cells in vitro. Opposite effects on cellular phenotype were observed after suppression of endogenous relaxin/RXFP1 expression or signaling. We showed an accelerated progression of prostate cancer in TRAMP males with transgenic relaxin overexpression and a longer survival of TRAMP, RXFP1-deficient males. Suppression of RXFP1 expression in PC3 xenografts in nude mice using siRNA intratumoral injections resulted in decrease of tumor size, cell proliferation, and metastasis rate.
PMCID: PMC2945500  PMID: 19416223
Prostate cancer; Relaxin; RXFP1; siRNA; TRAMP

Results 1-3 (3)