Disease relevance of ESX1

• Moreover, ESX1L is equally expressed in IUGR and normal placentas, and shows the same methylation pattern in the presence of both random and skewed XCI [1].
• These findings provide evidence that ESX1L is not imprinted in human third-trimester placentas and there is no parent-of-origin effect of chromosome X associated with placental insufficiency [1].

High impact information on ESX1

• Using the Esx1 gene promoter as a model for a Dlx3-responsive gene, studies demonstrate two near consensus Dlx3 binding sites within the proximal 2.3 kb of the transcription start site [2].
• We also showed that the N-terminal ESXR1 fragment binds to the TAATGTTATTA sequence present within the first intron of the human K-ras gene and inhibits its expression at both mRNA and protein levels [3].
• ESXR1 is a human paired-like homeodomain-containing protein expressed primarily in the testis [3].
• In cells, the 65-kDa full-length ESXR1 protein is proteolytically processed into an N-terminal 45-kDa fragment containing the homeodomain, which localizes exclusively within the nucleus, and a C-terminal 20-kDa fragment consisting of a proline-rich repeat region, which is located in the cytoplasm [3].
• In this work, we demonstrated that the N-terminal ESXR1 fragment specifically recognizes the TAATNNNATTA P3 consensus sequence for the paired-like homeodomain and functions as a sequence-specific transcriptional repressor [3].

Biological context of ESX1

• Our results indicate that proteolytic processing of ESXR1 plays a role in concerted regulation of the cell cycle and transcription in human cells [4].
• Accordingly, elevation of ESXR1 level results in accumulation of cyclin A and cyclin B1 and thereby provokes M-phase arrest [4].
• ESXR1 has been localized to human Xq22.1-q22.3, the same region of synteny shared by the map position of Esx1 [5].
• Unlike Esx1, ESXR1 contains 12 repeats of a unique nine amino acid motif, PPMAP(V/L)PPG, located C-terminal to the homeodomain [5].
• A novel human homeobox gene related to the mouse Esx1 homeobox gene, which we have designated ESXR1, has been identified [5].

Anatomical context of ESX1

• In adult tissues, ESXR1 is primarily expressed in the testis [4].
• The mRNA expression of the ESX1L gene was analyzed by RT-PCR and in situ hybridization in human normal cytogenetically placentas, of different gestational ages [6].
• ESX1L mRNA expression was more pronounced in trophoblast cells of terminal villi than in intermediate and stem villi [6].
• We investigated the imprinting status of the human orthologous Esx1 gene (ESX1L) in placental samples of four normal full-term and 13 IUGR female fetuses, in which we determined the XCI pattern [1].

Associations of ESX1 with chemical compounds

• ESXR1 and Esx1 share 65% identity within their homeodomains and have glutamic acid-rich and proline-rich N- and C-terminal regions, respectively [5].

Regulatory relationships of ESX1

• Paired-like homeodomain protein ESXR1 possesses a cleavable C-terminal region that inhibits cyclin degradation [4].

Other interactions of ESX1

• In this work, we screened human cDNAs that can rescue yeast Saccharomyces cerevisiae from lethality caused by ectopic expression of human cyclin E and isolated a cDNA encoding ESXR1, a paired-like homeodomain-containing protein with a unique C-terminal proline-rich repeat region [4].
• ESX1L, a novel X chromosome-linked human homeobox gene expressed in the placenta and testis [5].
• Identification of ESXR1 as a transcriptional repressor of K-ras has an important implication for the development of cancer therapy that inhibits oncogenic K-Ras expression [3].

Analytical, diagnostic and therapeutic context of ESX1

• Our RT-PCR analysis showed that ESX1L mRNA is expressed from 5 weeks of gestation until term, suggesting a role not only in trophoblast differentiation but also in the maintenance of the villi and microvasculature [6].
• Real-time PCR quantitation showed ESX1L levels in control placentae decreased between pre-term and term [0.7 +/- 0.20 (27-35 weeks, n = 13) versus 0.2 +/- 0.06 (36-41 weeks, n = 12), t-test, P < 0.005] [7].

References