Prolactin Receptor Isoforms as the Basis of Tissue-Specific Action of Prolactin in the Norm and Pathology

Abramicheva, P A; Смирнова, О. В.

doi:10.1134/s0006297919040011

Cited by 36 publications

(30 citation statements)

References 127 publications

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“…PRL binding to the long isoform results in a wide range of activation of numerous kinases, including JAK2, STAT, MAPK, PI3K, and AKT [13,14]. In contrast, the short isoforms suppress signaling through the JAK2-STAT pathway due to heterodimer formation with the long isoform [15]. The short isoforms also exhibit long isoform-independent activities upon PRL engagement [16].…”

Section: Introductionmentioning

confidence: 99%

“…The short isoforms also exhibit long isoform-independent activities upon PRL engagement [16]. Thus, the activated pathway and the resulting PRL effector functions depend on the isoform and cell type in which the PRL-receptor is engaged [15,17,18]. For instance, PRL promotes the proliferation, differentiation, and survival of mammary glands through JAK-STAT5 and PI3K-AKT signaling [19], while it activates STAT1 and STAT5 in endometrial cells [20].…”

Section: Introductionmentioning

confidence: 99%

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Prolactin Rescues Immature B Cells from Apoptosis-Induced BCR-Aggregation through STAT3, Bcl2a1a, Bcl2l2, and Birc5 in Lupus-Prone MRL/lpr Mice

Flores-Fernández

Aponte-López

Suárez-Arriaga

et al. 2021

Cells

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Self-reactive immature B cells are eliminated through apoptosis by tolerance mechanisms, failing to eliminate these cells results in autoimmune diseases. Prolactin is known to rescue immature B cells from B cell receptor engagement-induced apoptosis in lupus-prone mice. The objective of this study was to characterize in vitro prolactin signaling in immature B cells, using sorting, PCR array, RT-PCR, flow cytometry, and chromatin immunoprecipitation. We found that all B cell maturation stages in bone marrow express the prolactin receptor long isoform, in both wild-type and MRL/lpr mice, but its expression increased only in the immature B cells of the latter, particularly at the onset of lupus. In these cells, activation of the prolactin receptor promoted STAT3 phosphorylation and upregulation of the antiapoptotic Bcl2a1a, Bcl2l2, and Birc5 genes. STAT3 binding to the promoter region of these genes was confirmed through chromatin immunoprecipitation. Furthermore, inhibitors of prolactin signaling and STAT3 activation abolished the prolactin rescue of self-engaged MRL/lpr immature B cells. These results support a mechanism in which prolactin participates in the emergence of lupus through the rescue of self-reactive immature B cell clones from central tolerance clonal deletion through the activation of STAT3 and transcriptional regulation of a complex network of genes related to apoptosis resistance.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prolactin Rescues Immature B Cells from Apoptosis-Induced BCR-Aggregation through STAT3, Bcl2a1a, Bcl2l2, and Birc5 in Lupus-Prone MRL/lpr Mice

Flores-Fernández

Aponte-López

Suárez-Arriaga

et al. 2021

Cells

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“…Studies in breast and prostate cancers revealed that there are multiple putative isoforms of the human PRLR gene (Abramicheva and Smirnova, 2019;Griffith et al, 2016;Shemanko, 2016), presumably a consequence of alternative splicing and in some instances a result of mutations. As a consequence, we conducted a search to determine the putative predicted isoforms or transcript variants associated with PRLR siRNA used in this study.…”

Section: Nature Of Sirnas and Putative Prlr Isoforms In Hlmentioning

confidence: 99%

Immunohistochemical localization of prolactin receptor (PRLR) to Hodgkin’s and Reed-Sternberg cells of Hodgkin’s lymphoma

et al. 2021

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Prolactin receptor (PRLR), a type-1 cytokine receptor, is overexpressed in a number of cancer types. It has attracted much attention for putative pro-oncogenic roles, which however, remains controversial in some malignancies. In this study, we reported the localization of PRLR to the Hodgkin's and Reed-Sternberg (HRS) cells of Hodgkin's lymphoma (HL), a neoplasm of predominantly B cell origin. Immunohistochemistry performed on 5μm thick FFPE sections revealed expression of PRLR in HRS cells. Cellular immunofluorescence experiments showed that the HL-derived cell lines, Hs445, KMH2 and L428 overexpressed PRLR. The PRLR immunofluorescent signal was depleted after treating the cell lines with 10 μM of siRNA for 48 h. We also tested whether PRLR is involved in the growth of HL, in vitro. One-way analysis of variance (ANOVA) on cell growth data obtain from WST-1 cell proliferation assay and trypan blue exclusion assay and hemocytometry showed that siRNAdepletion of PRLR expression resulted in decreased growth in all three cell lines. These results offered only a short insight into the involvement of PRLR in HL. As a result, further investigation is required to decipher the precise role(s) of PRLR in the pathogenesis of HL.

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“…It is known that the long PRL isoforms signal through the JAK-STAT and PI3K-AKT pathways [41,42]. We determined the signaling components associated with the PRL receptor upon activation with recombinant PRL in T FH cells differentiated in vitro.…”

Section: Prolactin Promoted Stat3 Phosphorylation In T Fh Cellsmentioning

confidence: 99%

Prolactin Increases the Frequency of Follicular T Helper Cells with Enhanced IL21 Secretion and OX40 Expression in Lupus-Prone MRL/lpr Mice

Alemán-García

Vaquero-García

Flores-Fernández

et al. 2021

Journal of Immunology Research

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Systemic lupus erythematosus is characterized by high levels of IgG class autoantibodies that contribute to the pathophysiology of the disease. The formation of these autoantibodies occurs in the germinal centers, where there is cooperation between follicular T helper cells (TFH) and autoreactive B cells. Prolactin has been reported to exacerbate the clinical manifestations of lupus by increasing autoantibody concentrations. The objective of this study was to characterize the participation of prolactin in the differentiation and activation of TFH cells, by performing in vivo and in vitro tests with lupus-prone mice, using flow cytometry and real-time PCR. We found that TFH cells express the long isoform of the prolactin receptor and promoted STAT3 phosphorylation. Receptor expression was higher in MRL/lpr mice and correlative with the manifestations of the disease. Although prolactin does not intervene in the differentiation of TFH cells, it does favor their activation by increasing the percentage of TFH OX40+ and TFH IL21+ cells, as well as leading to high serum concentrations of IL21. These results support a mechanism in which prolactin participates in the emergence of lupus by inducing overactive TFH cells and perhaps promoting dysfunctional germinal centers.

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Prolactin Receptor Isoforms as the Basis of Tissue-Specific Action of Prolactin in the Norm and Pathology

Cited by 36 publications

References 127 publications

Prolactin Rescues Immature B Cells from Apoptosis-Induced BCR-Aggregation through STAT3, Bcl2a1a, Bcl2l2, and Birc5 in Lupus-Prone MRL/lpr Mice

Prolactin Rescues Immature B Cells from Apoptosis-Induced BCR-Aggregation through STAT3, Bcl2a1a, Bcl2l2, and Birc5 in Lupus-Prone MRL/lpr Mice

Immunohistochemical localization of prolactin receptor (PRLR) to Hodgkin’s and Reed-Sternberg cells of Hodgkin’s lymphoma

Prolactin Increases the Frequency of Follicular T Helper Cells with Enhanced IL21 Secretion and OX40 Expression in Lupus-Prone MRL/lpr Mice

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