scholarly journals Regulation of the Follicle-Stimulating Hormone β Gene by the LHX3 LIM-Homeodomain Transcription Factor

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 4866-4879 ◽  
Author(s):  
Brooke E. West ◽  
Gretchen E. Parker ◽  
Jesse J. Savage ◽  
Parinda Kiratipranon ◽  
Katherine S. Toomey ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Quantitative Methods ◽  
Proximal Region ◽  
Dominant Negative ◽  
Β Subunit ◽  
Homeodomain Transcription Factor ◽  
Functional Conservation ◽  
Drosophila Protein ◽  
Lim Homeodomain

Abstract FSH is a critical hormone regulator of gonadal function that is secreted from the pituitary gonadotrope cell. Human patients and animal models with mutations in the LHX3 LIM-homeodomain transcription factor gene exhibit complex endocrine diseases, including reproductive disorders with loss of FSH. We demonstrate that in both heterologous and pituitary gonadotrope cells, specific LHX3 isoforms activate the FSH β-subunit promoter, but not the proximal LHβ promoter. The related LHX4 mammalian transcription factor can also induce FSHβ promoter transcription, but the homologous Drosophila protein LIM3 cannot. The actions of LHX3 are specifically blocked by a dominant negative LHX3 protein containing a Krüppel-associated box domain. Six LHX3-binding sites were characterized within the FSHβ promoter, including three within a proximal region that also mediates gene regulation by other transcription factors and activin. Mutations of the proximal binding sites demonstrate their importance for LHX3 induction of the FSHβ promoter and basal promoter activity in gonadotrope cells. Using quantitative methods, we show that the responses of the FSHβ promoter to activin do not require induction of the LHX3 gene. By comparative genomics using the human FSHβ promoter, we demonstrate structural and functional conservation of promoter induction by LHX3. We conclude that the LHX3 LIM homeodomain transcription factor is involved in activation of the FSH β-subunit gene in the pituitary gonadotrope cell.

scholarly journals Activation of the Thyroid-Stimulating Hormone β-Subunit Gene by LIM Homeodomain Transcription Factor Lhx2

Endocrinology ◽  
2007 ◽  
Vol 148 (7) ◽  
pp. 3468-3476 ◽  
Author(s):  
Kee K. Kim ◽  
Seok B. Song ◽  
Kwang I. Kang ◽  
Myungchull Rhee ◽  
Kyoon Eon Kim
Keyword(s):  
Transcription Factor ◽  
Reporter Gene ◽  
Thyroid Stimulating Hormone ◽  
Β Subunit ◽  
Subunit Gene ◽  
Mobility Shift ◽  
Glycoprotein Hormone ◽  
Α Subunit ◽  
Homeodomain Transcription Factor ◽  
Lim Homeodomain

Although there is evidence that the LIM homeodomain transcription factor, Lhx2, can stimulate transcription of the glycoprotein hormone α-subunit gene, the role of Lhx2 in regulating TSH β-subunit has not been established. In the present studies, the ability of Lhx2 to regulate transcription of the TSH β-subunit gene was examined. In the thyrotrope-derived TαT1 cell line, Lhx2 expression was found to be induced by treatment with either TRH or cAMP, consistent with the possibility that Lhx2 may play a role in mediating the ability of this signaling pathway to stimulate TSH gene expression. Transient, forced overexpression of Lhx2 stimulated activity of a TSH β-subunit reporter gene. Deletion studies provided evidence that the −177 to −79 region of the TSH β-subunit promoter was necessary for stimulation of reporter gene activity by Lhx2. A gel mobility shift assay provided the evidence that Lhx2 can bind to this region of DNA. DNase I footprinting studies demonstrated that two distinct regions of the TSHβ promoter, −118 to −108 and −86 to −68, are protected by Lhx2 from nuclease digestion. These regions contain repeats of the sequence, 5′-(G/T)CAAT(T/A)-3′. Mutation of this sequence, especially in the −86 to −68 region, substantially decreased Lhx2 responsiveness of the TSH β-subunit reporter gene. In addition, a DNA fragment containing the −177 to −79 region of the TSHβ promoter was found to confer Lhx2 responsiveness to a minimal promoter. These results provide multiple lines of evidence consistent with a role for Lhx2 in modulating expression of the TSH β-subunit gene.

scholarly journals Pituitary transcription factor Prop-1 stimulates porcine pituitary glycoprotein hormone α subunit gene expression

2006 ◽  
Vol 37 (2) ◽  
pp. 341-352 ◽  
Author(s):  
Takanobu Sato ◽  
Kousuke Kitahara ◽  
Takao Susa ◽  
Takako Kato ◽  
Yukio Kato
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Binding Sites ◽  
Gh3 Cells ◽  
Pituitary Hormone ◽  
Transcriptional Level ◽  
Β Subunit ◽  
Glycoprotein Hormone ◽  
Α Subunit

Recently, we have reported that a Prophet of Pit-1 homeodomain factor, Prop-1, is a novel transcription factor for the porcine follicle-stimulating hormone β subunit (FSHβ) gene. This study subsequently aimed to examine the role of Prop-1 in the gene expression of two other porcine gonadotropin subunits, pituitary glycoprotein hormone α subunit (αGSU), and luteinizing hormone β subunit (LHβ). A series of deletion mutants of the porcine αGSU (up to −1059 bp) and LHβ (up to −1277 bp) promoters were constructed in the reporter vector, fused with the secreted alkaline phosphatase gene (pSEAP2-Basic). Transient transfection studies using GH3 cells were carried out to estimate the activation of the porcine αGSU and LHβ promoters by Prop-1, which was found to activate the αGSU promoter of −1059/+12 bp up to 11.7-fold but not the LHβ promoter. Electrophoretic mobility shift assay and DNase I footprinting analysis revealed that Prop-1 binds to six positions, −1038/−1026, −942/−928, −495/−479, −338/−326, −153/−146, and −131/−124 bp, that comprise the A/T cluster. Oligonucleotides of six Prop-1 binding sites were directly connected to the minimum promoter of αGSU, fused in the pSEAP2-Basic vector, followed by transfecting GH3 cells to determine the cis-acting activity. Finally, we concluded that at least five Prop-1 binding sites are the cis-acting elements for αGSU gene expression. The present results revealed a notable feature of the proximal region, where three Prop-1-binding sites are close to and/or overlap the pituitary glycoprotein hormone basal element, GATA-binding element, and junctional regulatory element. To our knowledge, this is the first demonstration of the role of Prop-1 in the regulation of αGSU gene expression. These results, taken together with our previous finding that Prop-1 is a transcription factor for FSHβ gene, confirm that Prop-1 modulates the synthesis of FSH at the transcriptional level. On the other hand, the defects of Prop-1 are known to cause dwarfism and combined pituitary hormone deficiency accompanying hypogonadism. Accordingly, the present observations provide a novel view to understand the hypogonadism caused by Prop-1 defects at the molecular level through the regulatory mechanism of αGSU and FSHβ gene expressions.

A Conserved Mechanism of Transcription Factor Competition Controls Hematopoietic Progenitor Self-Renewal.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 91-91
Author(s):  
Shane R. Horman ◽  
Chinamenveni S. Velu ◽  
Tristan Bourdeau ◽  
Avinash Baktula ◽  
Jinfang Zhu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transcription Factor ◽  
Binding Sites ◽  
Bone Marrow Cells ◽  
Dominant Negative ◽  
Wild Type ◽  
Hematopoietic Progenitor ◽  
Self Renewal ◽  
Conditional Deletion

Abstract An intrinsic mechanism of self-renewal is critical for the maintenance of hematopoietic stem cells (HSC), but this HSC function is extinguished during differentiation of progenitors. Here we show that the self-renewal capacity of hematopoietic progenitor cells is regulated through physical competition for occupancy of select DNA binding sites. Initially, we found that conditional deletion of the Growth factor independent-1 (Gfi1) gene results in the accumulation of abnormally persistent myeloid progenitors in vivo. Specifically, while germline Gfi1 deletion induces defective HSC self renewal and a block to granulopoiesis, we find that conditional deletion of Gfi1 induces a severe but transient block to neutrophil development with repopulation of the bone marrow by the remaining wild type HSC within 8 weeks post deletion. However, even though normal levels of granulocyte colony forming units (G-CFU) returned by 8 weeks post deletion, an abnormal Gfi1−/− myeloid progenitor remained in the bone marrow in vivo. Subsequently, we find in vitro that both wild-type bone marrow cells expressing Gfi1-dominant-negative mutants, and Gfi1−/− Lin- bone marrow contain cells that replate indefinitely. We hypothesized that Gfi1 is critical to extinguish self renewal in hematopoietic progenitors. In seemingly unrelated work, we discovered antagonism between the drosophila orthologs of Gfi1 and the Hoxa9/Pbx1/Meis1 transcription factor complex during drosophila embryo segmentation. We extended our drosophila findings to discover that a subset of mammalian DNA regulatory sequences encode DNA binding sites for both Gfi1 and Hoxa9/Pbx1/Meis1. These DNA sequences are able to bind either factor, and function as a molecular switch. Interestingly, composite Gfi1/ Hoxa9/Pbx1/Meis1 binding sites are present in the regulatory regions of the gene encoding Hoxa9. We note that Gfi1 expression is normally induced, while Hoxa9 expression is down-regulated, during the transition from common myeloid progenitor (CMP) to the granulocyte-monocyte progenitor (GMP). CMP have greater self renewal potential than GMP. Conditional deletion of Gfi1 in sorted CMP or GMP both increases Hoxa9 expression and generates progenitors capable of replating indefinitely in vitro. Thus, Gfi1 is critical to limit self renewal in these progenitors. Deregulated Hoxa9 expression or activity appears pivotal to this new Gfi1-null phenotype, because Gfi1 dominant-negative mutants immortalize wild-type (or Hoxa7−/−) but not Hoxa9−/− bone marrow cells in vitro. An abnormal gain of self-renewal can unleash the leukemic potential of progenitor cells. We find that both limiting Gfi1 gene dosage and expression of Gfi1 dominant-negative mutants significantly increases Nup98-Hoxa9-mediated colony formation. In contrast, forced expression of Gfi1 prevents Nup98-Hoxa9 immortalization. Notably, the expression of Hoxa9 (independent of cases with Nup98-Hoxa9 fusions) has been reported to be of significant prognostic value in human acute myeloid leukemia. In conclusion, Gfi1 and the Hoxa9/Pbx1/Meis1 complex compete to control the expression of genes (such as Hoxa9) which are critical to extinguish self renewal and limit the leukemogenic potential of hematopoietic progenitors. The antagonism between these transcription factor complexes is conserved from drosophila segment formation to mammalian hematopoietic progenitor biology.

scholarly journals The LIM-homeodomain transcription factor Islet2a promotes angioblast migration

2016 ◽  
Vol 414 (2) ◽  
pp. 181-192 ◽  
Author(s):  
Ryan E. Lamont ◽  
Chang.-Yi. Wu ◽  
Jae.-Ryeon. Ryu ◽  
Wendy Vu ◽  
Paniz Davari ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Homeodomain Transcription Factor ◽  
Lim Homeodomain

Expression and function of the LIM-homeodomain transcription factor Islet-1 in the developing and mature vertebrate retina

2015 ◽  
Vol 138 ◽  
pp. 22-31 ◽  
Author(s):  
Ruth Bejarano-Escobar ◽  
Guadalupe Álvarez-Hernán ◽  
Ruth Morona ◽  
Agustín González ◽  
Gervasio Martín-Partido ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Homeodomain Transcription Factor ◽  
Vertebrate Retina ◽  
Islet 1 ◽  
And Function ◽  
Lim Homeodomain

scholarly journals The zinc finger transcription factor ZFHX1A is linked to cell proliferation by Rb–E2F1

2007 ◽  
Vol 408 (1) ◽  
pp. 79-85 ◽  
Author(s):  
Yongqing Liu ◽  
Mary E. Costantino ◽  
Diego Montoya-Durango ◽  
Yujiro Higashi ◽  
Douglas S. Darling ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Dominant Negative ◽  
Proliferating Cells ◽  
Zinc Finger Transcription Factor ◽  
Dominant Negative Form ◽  
Repressor Complex ◽  
E Box ◽  
Cell Cycle Pathway ◽  
Negative Form

ZFHX1A is expressed in proliferating cells in the developing embryo, and in the present study we provide evidence that its expression is confined to proliferating cells through dependence on the Rb (retinoblastoma protein) family/E2F cell cycle pathway. Mutation of the Rb or E2F1 genes lead to induction of ZFHX1A mRNA, implying that the Rb–E2F1 repressor complex is important for repression of ZFHX1A. This repression is associated with recruitment of an E2F–Rb–histone deacetylase repressor complex to the promoter. A dominant-negative form of E2F1 inhibited ZFHX1A expression in p16INK4a(−) cells where Rb is constitutively hyperphosphorylated and inactive, suggesting that E2F can contribute to ZFHX1A transactivation in the absence of functional Rb. ZFHX1A is an E-box-binding transcription factor whose binding sites overlap with those bound by Snail1 and 2, and ZFHX1B/SIP1 (leading to at least partially overlapping function; for example, each of the proteins can repress E-cadherin expression). We found that expression of Snail1 and ZFHX1B/SIP1 is also regulated by E2Fs, but in contrast with ZFHX1A this regulation is Rb-family-independent. Snail2 expression was unaffected by either E2F or the Rb family. We propose that the differential effects of the Rb family/E2F pathway on expression of these E-box-binding proteins are important in maintaining their distinct patterns (and thus distinct functions) during embryogenesis.

scholarly journals The LIM-homeodomain transcription factor Lmx1b plays a crucial role in podocytes

2002 ◽  
Vol 109 (8) ◽  
pp. 1073-1082 ◽  
Author(s):  
Claudia Rohr ◽  
Jürgen Prestel ◽  
Laurence Heidet ◽  
Hiltraud Hosser ◽  
Wilhelm Kriz ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Crucial Role ◽  
Homeodomain Transcription Factor ◽  
Lim Homeodomain

scholarly journals Anti-osteogenic function of a LIM-homeodomain transcription factor LMX1B is essential to early patterning of the calvaria

2018 ◽  
Vol 443 (2) ◽  
pp. 103-116 ◽  
Author(s):  
Jeffry M. Cesario ◽  
André Landin Malt ◽  
Jong Uk Chung ◽  
Michael P. Khairallah ◽  
Krishnakali Dasgupta ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Homeodomain Transcription Factor ◽  
Lim Homeodomain
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