HGNC Approved Gene Symbol: PRL
Cytogenetic location: 6p22.3 Genomic coordinates (GRCh38): 6:22,287,246-22,302,835 (from NCBI)
Truong et al. (1984) cloned the PRL gene, which encodes a 199-amino acid protein.
Larrea et al. (1987) presented the results of family studies suggesting that there is a familial factor determining the occurrence of the 'big-big' form as the predominant immunoreactive PRL species in blood.
Evans et al. (1989) found that the cell line used in their mapping studies was heterozygous for PRL DNA fragment lengths generated by HpaII but not MspI digestion, indicating that the 2 copies of the PRL gene in the cell line are differentially methylated. This novel methylation RFLP was used to corroborate the regional PRL assignment.
Sun et al. (1997) noted that human PRL binds Zn(2+), but that the function of the binding was unknown. They studied the effect of human H27A-PRL, a mutant that does not bind Zn(2+) on PRL production in stably transfected rat pituitary cells. Unexpectedly, clones transfected with H27A-PRL made little rat PRL. Clones transfected with vector alone, with wildtype human PRL, or with human K69A-PRL made amounts of rat PRL in the same range. Human H27A-PRL was not efficiently secreted, 20 to 40% of newly synthesized H27A-PRL was degraded by 60 min, and there was usually a delay in release of newly synthesized H27A-PRL. The authors concluded that Zn(2+) binding stabilizes PRL in the secretory pathway; the instability of the mutant protein may trigger effects that suppress rat PRL production directly or that result in selection of clones with low rat PRL production.
As pointed out by DiMattia (1998), the PRL gene possesses alternative tissue-specific promoters that are located 5,563 basepairs apart. The 5-prime promoter is specific for expression of prolactin in the decidualized human endometrium and in lymphoblastoid cells such as the human cell line IM-9-P3; the downstream promoter is specific for expression in the pituitary lactotrope and is under the control of the POU-homeodomain transcription factor PIT1 (173110). Transcriptional control of the nonpituitary start site is linked to the differentiation of the endometrial stromal cell into the decidual cell during the secretory phase of the ovulatory cycle (DiMattia et al., 1990, Gellersen et al., 1994).
By deletion analysis of the human PRL promoter in endometrial stromal cells decidualized in vitro, Watanabe et al. (2001) demonstrated a 536-bp enhancer located between nucleotides -2040 and -1505 in the 5-prime-flanking region. DNase I footprint analysis of decidualized endometrial stromal cells revealed 3 protected regions, FP1-FP3. Transfection of overlapping 100-bp fragments of the 536-bp enhancer indicated that FP1 and FP3 each conferred enhancer activity. Gel shift assays indicated that both FP1 and FP3 bind AP1 (165160), and that JUND (165162) and FOSL2 (601575) are components of the AP1 complex in decidual fibroblasts. Mutation of the AP1 binding site in either FP1 or FP3 decreased enhancer activity by approximately 50%, while mutation of both sites almost completely abolished activity.
Brisken et al. (2002) found that prolactin induced Igf2 (147470) mRNA and Igf2 induced cyclin D1 (CCND1; 168461) protein expression in mouse mammary epithelial cultures. Alveologenesis was retarded in both Igf2-deficient cells and cyclin D1-deficient cells. Igf2 and prolactin receptor (PRLR; 176761) mRNAs colocalized in mammary epithelium. Brisken et al. (2002) concluded that IGF2 is a mediator of prolactin-induced alveologenesis and that prolactin, IGF2, and cyclin D1 are components of a developmental pathway in mammary gland.
Ling et al. (2003) demonstrated that PRL directly affects and inhibits the lipoprotein lipase (LPL; 609708) activity in human adipose tissue via functional PRL receptors, suggesting an important role for PRL in regulating adipose tissue metabolism during lactation.
Matsuda et al. (2004) found that mouse mammary glands stimulated by prolactin expressed genes essential for serotonin biosynthesis, including Tph (191060). Tph mRNA was elevated during pregnancy and lactation, and serotonin was detected in the mammary epithelium and in milk. Tph was induced by prolactin in mammosphere cultures and by milk stasis in nursing dams, suggesting that expression of TPH is controlled by milk filling in the alveoli. Serotonin suppressed beta-casein (115460) expression and caused shrinkage of mammary alveoli. Conversely, disruption of the Tph gene or antiserotonergic drugs enhanced secretory features and alveolar dilation. Matsuda et al. (2004) concluded that autocrine-paracrine serotonin signaling is an important regulator of mammary homeostasis and early involution.
In addition to expression in pituitary and placenta and functions in growth and reproduction, PRL, GH, and placental lactogen (CSH1) are expressed in endothelial cells and have angiogenic effects. Ge et al. (2007) found that BMP1 (112264) and BMP1-like proteinases processed PRL and GH in vitro and in vivo to produce approximately 17-kD N-terminal fragments with antiangiogenic activity.
The PRL gene shows homology to the genes for growth hormone (GH; see 139250) and chorionic somatomammotropin (CS; see 150200), but not as close homology as these two bear to each other (Cooke et al., 1981). Only 16% sequence homology of the growth hormone and prolactin gene has been found (Shome and Parlow, 1977).
Truong et al. (1984) determined that the PRL gene contains 5 exons and spans about 10 kb.
Owerbach et al. (1981) did Southern blot analyses of DNA from human-mouse cell hybrids to show that the prolactin gene is located on chromosome 6 (Owerbach et al., 1981).
By somatic cell hybridization, Taggart et al. (1987) narrowed the assignment of the PRL gene to 6pter-p21.1.
Evans et al. (1988, 1989) mapped the prolactin gene in a series of overlapping deletions of chromosome 6 produced by gamma-irradiation of a human lymphoblastoid cell line followed by selection for HLA antigen-loss mutants. A densitometric approach was used to locate PRL in the interval 6p22.2-p21.3, distal to HLA-C.
Neurogenesis occurs in the olfactory system of the adult brain throughout life in both vertebrates and invertebrates. Shingo et al. (2003) demonstrated that the production of neuronal progenitors is stimulated in the forebrain subventricular zone of female mice during pregnancy and that this effect is mediated by the hormone prolactin. The progenitors then migrate to produce new olfactory interneurons, a process likely to be important for maternal behavior, because olfactory discrimination is critical for recognition and rearing of offspring. Neurogenesis occurs even in females that mate with sterile males. Shingo et al. (2003) concluded that their findings imply that forebrain olfactory neurogenesis may contribute to adaptive behaviors in mating and pregnancy.
The regional assignment of prolactin to the short arm of chromosome 6 is of interest because of possible association between prolactin-secreting adenomas and specific HLA alleles (Farid et al., 1980).
In a woman with recurrent spontaneous abortions, D'Alessandro et al. (1992) found idiopathic hypoprolactinemia and mosaicism for a partial deletion of 6p. The breakpoint was at 6p23.
Brisken, C., Ayyannan, A., Nguyen, C., Heineman, A., Reinhardt, F., Tan, J., Dey, S. K., Dotto, G. P., Weinberg, R. A. IGF-2 is a mediator of prolactin-induced morphogenesis in the breast. Dev. Cell 3: 877-887, 2002. Note: Erratum: Dev. Cell 4: 283 only, 2003. [PubMed: 12479812] [Full Text: https://doi.org/10.1016/s1534-5807(02)00365-9]
Cooke, N. E., Baxter, J. D. Structural analysis of the prolactin gene suggests a separate origin for its 5-prime end. Nature 297: 603-606, 1982. [PubMed: 6283362] [Full Text: https://doi.org/10.1038/297603a0]
Cooke, N. E., Coit, D., Shine, J., Baxter, J. D., Martial, J. A. Human prolactin: cDNA structural analysis and evolutionary comparisons. J. Biol. Chem. 256: 4007-4016, 1981. [PubMed: 6260780]
D'Alessandro, E., Santiemma, V., Lo Re, M. L., Ligas, C., Del Porto, G. 6p23 deletion mosaicism in a woman with recurrent abortions and idiopathic hypoprolactinemia. Am. J. Med. Genet. 44: 220-222, 1992. [PubMed: 1456295] [Full Text: https://doi.org/10.1002/ajmg.1320440219]
DiMattia, G. E., Gellersen, B., Duckworth, M. L., Friesen, H. G. Human prolactin gene expression: the use of an alternative noncoding exon in decidua and the IM-9-P3 lymphoblast cell line. J. Biol. Chem. 265: 16412-16421, 1990. [PubMed: 1697858]
DiMattia, G. E. Personal Communication. London, Ontario, Canada 3/23/1998.
Evans, A. M., Petersen, J. W., Sekhon, G. S., DeMars, R. I. Use of human lymphoblastoid deletion mutants to map the prolactin gene on human chromosome 6p. (Abstract) Am. J. Hum. Genet. 43: A143 only, 1988.
Evans, A. M., Petersen, J. W., Sekhon, G. S., DeMars, R. Mapping of prolactin and tumor necrosis factor-beta genes on human chromosome 6p using lymphoblastoid cell deletion mutants. Somat. Cell Molec. Genet. 15: 203-213, 1989. [PubMed: 2567059] [Full Text: https://doi.org/10.1007/BF01534871]
Farid, N. R., Noel, E. P., Sampson, L., Russell, N. A. Prolactin-secreting adenomata are possibly associated with HLA-B8. Tissue Antigens 15: 333-335, 1980. [PubMed: 7466775] [Full Text: https://doi.org/10.1111/j.1399-0039.1980.tb00926.x]
Ge, G., Fernandez, C. A., Moses, M. A., Greenspan, D. S. Bone morphogenetic protein 1 processes prolactin to a 17-kDa antiangiogenic factor. Proc. Nat. Acad. Sci. 104: 10010-10015, 2007. [PubMed: 17548836] [Full Text: https://doi.org/10.1073/pnas.0704179104]
Gellersen, B., Kempf, R., Telgmann, R., DiMattia, G. E. Nonpituitary human prolactin gene transcription is independent of Pit-1 and differentially controlled in lymphocytes and in endometrial stroma. Molec. Endocr. 8: 356-373, 1994. [PubMed: 8015553] [Full Text: https://doi.org/10.1210/mend.8.3.8015553]
Larrea, F., Escorza, A., Granados, J., Valencia, X., Valero, A., Cravioto, M. C., Perez-Palacios, G. Familial occurrence of big-big prolactin as the predominant immunoreactive human prolactin species in blood. Fertil. Steril. 47: 956-963, 1987. [PubMed: 3595901]
Ling, C., Svensson, L., Oden, B., Weijdegard, B., Eden, B., Eden, S., Billig, H. Identification of functional prolactin (PRL) receptor gene expression: PRL inhibits lipoprotein lipase activity in human white adipose tissue. J. Clin. Endocr. Metab. 88: 1804-1808, 2003. [PubMed: 12679477] [Full Text: https://doi.org/10.1210/jc.2002-021137]
Matsuda, M., Imaoka, T., Vomachka, A. J., Gudelsky, G. A., Hou, Z., Mistry, M., Bailey, J. P., Nieport, K. M., Walther, D. J., Bader, M., Horseman, N. D. Serotonin regulates mammary gland development via an autocrine-paracrine loop. Dev. Cell 6: 193-203, 2004. [PubMed: 14960274] [Full Text: https://doi.org/10.1016/s1534-5807(04)00022-x]
Owerbach, D., Rutter, W. J., Cooke, N. E., Martial, J. A., Shows, T. B. The prolactin gene is located on chromosome 6 in humans. Science 212: 815-816, 1981. [PubMed: 7221563] [Full Text: https://doi.org/10.1126/science.7221563]
Shingo, T., Gregg, C., Enwere, E., Fujikawa, H., Hassam, R., Geary, C., Cross, J. C., Weiss, S. Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science 299: 117-120, 2003. [PubMed: 12511652] [Full Text: https://doi.org/10.1126/science.1076647]
Shome, B., Parlow, A. F. Human pituitary prolactin (hPRL): the entire linear amino acid sequence. J. Clin. Endocr. Metab. 45: 1112-1115, 1977. [PubMed: 925136] [Full Text: https://doi.org/10.1210/jcem-45-5-1112]
Sun, Z., Lee, M. S., Rhee, H. K., Arrandale, J. M., Dannies, P. S. Inefficient secretion of human H27A-prolactin, a mutant that does not bind Zn(2+). Molec. Endocr. 11: 1544-1551, 1997. [PubMed: 9280069] [Full Text: https://doi.org/10.1210/mend.11.10.0002]
Taggart, R. T., Mohandas, T. K., Bell, G. I. Assignment of the human preprogastricsin (PGC) to chromosome 6 and regional localization of PGC (6pter-p21.1), prolactin PRL (6pter-p21.1). (Abstract) Cytogenet. Cell Genet. 46: 701-702, 1987.
Truong, A. T., Duez, C., Belayew, A., Renard, A., Pictet, R., Bell, G. I., Martial, J. A. Isolation and characterization of the human prolactin gene. EMBO J. 3: 429-437, 1984. [PubMed: 6325171] [Full Text: https://doi.org/10.1002/j.1460-2075.1984.tb01824.x]
Watanabe, K., Kessler, C. A., Bachurski, C. J., Kanda, Y., Richardson, B. D., Stanek, J., Handwerger, S., Brar, A. K. Identification of a decidua-specific enhancer on the human prolactin gene with two critical activator protein 1 (AP-1) binding sites. Molec. Endocr. 15: 638-653, 2001. [PubMed: 11266514] [Full Text: https://doi.org/10.1210/mend.15.4.0623]