Disease relevance of KISS1

• Quantitative real-time reverse-transcription PCR of clinical melanoma samples showed that loss of CRSP3 expression correlated with decreased KISS1 expression and increased metastasis [1].
• Increased TXNIP expression inhibited metastasis and up-regulated KISS1 [1].
• Particularly, in the case of KISS1 and Mkk4, an important role for future treatment of patients with breast cancer brain metastatic lesions can be assumed [2].
• Low levels of expression of BRMS1 were observed in normal pregnancies, in molar pregnancies and in choriocarcinoma cell lines BeWo, JAR and JEG3 while, in striking contrast, the expression levels of INSL4, KiSS-1 and Kiss-1R were increased in both early placentas and molar pregnancies and were reduced in choriocarcinoma cells [3].
• We examined the genes encoding GPR54 and its putative endogenous ligand, kisspeptin-1, for mutations in a cohort of 30 patients with normosmic HH or delayed puberty [4].
• Similar to postmenopausal women, ovariectomy induced neuronal hypertrophy and increased KiSS-1 gene expression in the monkey infundibular nucleus [5].

High impact information on KISS1

• KiSS-1 is a human metastasis suppressor gene, that suppresses metastases of human melanomas and breast carcinomas without affecting tumorigenicity [6].
• RESULTS: A novel cDNA, designated KiSS-1, was isolated from malignant melanoma cells that had been suppressed for metastatic potential by the introduction of human chromosome 6 [7].
• Transfection of a full-length KiSS-1 cDNA into C8161 melanoma cells suppressed metastasis in an expression-dependent manner [7].
• The KiSS-1 cDNA encodes a predominantly hydrophilic, 164 amino acid protein with a polyproline-rich domain indicative of an SH3 ligand (binds to the homology 3 domain of the oncoprotein Src) and a putative protein kinase C-alpha phosphorylation site [7].
• Hybridization histochemistry indicated robust KiSS-1 and GPR54 mRNA expression in the region of the arcuate nucleus [8].

Chemical compound and disease context of KISS1

• Overexpression of KiSS1 in ovarian cancer cells inhibits cell migration induced by serum or lysophosphatidic acid (LPA), and colonization in soft agar, but not cell proliferation, representing the characteristics of a metastasis suppressor gene [9].

Biological context of KISS1

• However, KISS1 mapped to chromosome 1q32 [1].
• The highest levels of KiSS-1 gene expression were observed in placenta and brain [10].
• The findings in this study show, for the first time, KiSS1 down-regulation during the progression of melanoma in vivo and strongly suggest that inactivation of a tumor suppressor gene(s) mapping to 6q16.3-q23 by deletion or mutation coupled with LOH may lead to the down-regulation of KiSS1 [11].
• We also examined a correlation between loss of KiSS1 mRNA expression and loss of heterozygosity (LOH) of 6q16.3-q23 in 27 melanoma metastases [11].
• Although the overall rate of cell adhesion to extracellular matrix components was unaffected, KiSS-1 transfectants spread on immobilized type-IV collagen more rapidly than did control populations [12].

Anatomical context of KISS1

• Overexpression of AP-2alpha into highly metastatic breast cell lines did not alter KiSS-1 promoter-driven luciferase gene activity [13].
• These transcriptional expression profiles are in favor of a predominant role of INSL4, KiSS-1 and KiSS-1R in the control of the invasive and migratory properties of trophoblast cells [3].
• To further study the role of GPR54 signaling in the onset of primate puberty, we used the monkey to examine the ability of kisspeptin-10 to elicit the release of gonadotropin-releasing hormone (GnRH) precociously, and we describe the expression of GPR54 and KiSS-1 in the hypothalamus during the peripubertal period [8].
• Parental, vector-only transfectants and KiSS-1 transfectant clones were injected into the mammary fat pads of athymic nude mice and assessed for tumor growth and spontaneous metastasis to regional lymph nodes and lungs [12].
• We observed complete loss of KiSS-1 in all invasive tumors under study as compared to their respective normal urothelium [14].

Associations of KISS1 with chemical compounds

• Kisspeptin administration evoked robust LH and testosterone bursts and enhanced postgonadectomy LH concentrations, despite prevailing attenuation of gonadotropic axis in diabetic animals [15].
• We propose that photoperiod, via melatonin, modulates KiSS-1 signaling to drive the reproductive axis [16].
• Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats [15].
• The excitatory neuronal systems most prevalently involved in this process use glutamate and the peptide kisspeptin for neurotransmission/neuromodulation, whereas the most important inhibitory inputs are provided by gamma-aminobutyric acid (GABA)ergic and opiatergic neurons [17].
• The pattern of distribution of kp10 immunoreactivity in the hypothalamus suggests a role for kisspeptin in the estrogen-dependent regulation of GnRH and LH secretion in the ewe [18].

Physical interactions of KISS1

• Although MMP-9 expression is regulated by AP-1, Sp1, and Ets transcription factors, KiSS-1 did not alter the binding of these factors to the MMP-9 promoter [19].

Regulatory relationships of KISS1

• CRSP3 transfectant cells had up-regulated KISS1 and TXNIP expression and were suppressed for metastasis [1].
• Furthermore, we demonstrated that AP-2alpha directly interacted with Sp1 to form transcription complexes at two tandem Sp1-binding sites of the promoter to activate KiSS-1 transcription [13].
• We demonstrate that KiSS-1 expression is regulated by Sp1 elements within the first 100-bp region of the KiSS-1 promoter and that targeted deletion of a single GC-rich region spanning -93 to -58 interrupts Sp1- and DRIP-130-modulated transcriptional control of KiSS-1 expression [20].

Other interactions of KISS1

• Thus, we implicated a specific gene on chromosome 6 in the etiology of melanoma metastasis and identified potential up-stream regulators of KISS1 and TXNIP [1].
• Nevertheless, mounting clinical evidence, particularly the loss of KISS1 in metastases, correlates KISS1 and metastin receptor expression with human tumor progression [21].
• The identification and sequence of KiSS-1 (HGMW-approved symbol, KISS1), a human malignant melanoma metastasis-suppressor gene, was recently published [22].
• KiSS-1 has been shown to function as a tumor metastasis suppressor gene and reduce the number of metastases in different cancers [13].
• Thus, KiSS-1 diminishes MMP-9 expression by effecting reduced NF-kappaB binding to the promoter [19].

Analytical, diagnostic and therapeutic context of KISS1

• Quantitative reverse transcriptase-polymerase chain reaction was used to study the expression of AXOR12 and KiSS-1 in a variety of tissues [10].
• Northern blot analyses comparing mRNAs from a panel of human melanoma cells revealed that KiSS-1 mRNA expression occurred only in nonmetastatic melanoma cells [7].
• To additionally elucidate the role of KiSS1 in the progression of human melanoma in vivo, we examined KiSS1 mRNA expression in 51 melanocytic tumors with various stages of progression by in situ hybridization [11].
• Using in situ hybridization and immunohistochemistry, we show that KiSS-1 is expressed in the arcuate nucleus of LD hamsters [16].
• Accordingly, patients with low KiSS-1-expressing tumors had a significantly worse overall and disease-free survival [23].

References