Journal articles: 'Dbx1'

1

Takahashi, Masanori, and Noriko Osumi. "Pax6 regulates specification of ventral neurone subtypes in the hindbrain by establishing progenitor domains." Development 129, no. 6 (March 15, 2002): 1327–38. http://dx.doi.org/10.1242/dev.129.6.1327.

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Recent studies have shown that generation of different kinds of neurones is controlled by combinatorial actions of homeodomain (HD) proteins expressed in the neuronal progenitors. Pax6 is a HD protein that has previously been shown to be involved in the differentiation of the hindbrain somatic (SM) motoneurones and V1 interneurones in the hindbrain and/or spinal cord. To investigate in greater depth the role of Pax6 in generation of the ventral neurones, we first examined the expression patterns of HD protein genes and subtype-specific neuronal markers in the hindbrain of the Pax6 homozygous mutant rat. We found that Islet2 (SM neurone marker) and En1 (V1 interneurone marker) were transiently expressed in a small number of cells, indicating that Pax6 is not directly required for specification of these neurones. We also observed that domains of all other HD protein genes (Nkx2.2, Nkx6.1, Irx3, Dbx2 and Dbx1) were shifted and their boundaries became blurred. Thus, Pax6 is required for establishment of the progenitor domains of the ventral neurones. Next, we performed Pax6 overexpression experiments by electroporating rat embryos in whole embryo culture. Pax6 overexpression in the wild type decreased expression of Nkx2.2, but ectopically increased expression of Irx3, Dbx1 and Dbx2. Moreover, electroporation of Pax6 into the Pax6 mutant hindbrain rescued the development of Islet2-positive and En1-positive neurones. To know reasons for perturbed progenitor domain formation in Pax6 mutant, we examined expression patterns of Shh signalling molecules and states of cell death and cell proliferation. Shh was similarly expressed in the floor plate of the mutant hindbrain, while the expressions of Ptc1, Gli1 and Gli2 were altered only in the progenitor domains for the motoneurones. The position and number of TUNEL-positive cells were unchanged in the Pax6 mutant. Although the proportion of cells that were BrdU-positive slightly increased in the mutant, there was no relationship with specific progenitor domains. Taken together, we conclude that Pax6 regulates specification of the ventral neurone subtypes by establishing the correct progenitor domains.

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Du, Ailing, Xiaojing Wu, Hanhan Chen, Qing-Ran Bai, Xiao Han, Bin Liu, Xiaohu Zhang, Zhaoying Ding, Qin Shen, and Chunjie Zhao. "Foxg1 Directly Represses Dbx1 to Confine the POA and Subsequently Regulate Ventral Telencephalic Patterning." Cerebral Cortex 29, no. 12 (March 4, 2019): 4968–81. http://dx.doi.org/10.1093/cercor/bhz037.

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Abstract During early development, signaling centers, such as the cortical hem and the preoptic area (POA), are critical for telencephalic patterning. However, the mechanisms underlying the maintenance of signal centers are poorly understood. Here, we report that the transcription factor Foxg1 is required to confine the POA, a resource of Sonic Hedgehog (Shh) that is pivotal for ventral telencephalic development. Cell-specific deletion of Foxg1 achieved by crossing Foxg1fl/fl with Dbx1-cre or Nestin-CreER combined with tamoxifen induction results in a dramatic expansion of the POA accompanied by the significantly increased activity of the Shh signaling pathway. Ventral pattern formation was severely impaired. Moreover, we demonstrated that Foxg1 directly represses Dbx1 to restrict the POA. Furthermore, we found that the ventral pallium was expanded, which might also contribute to the observed patterning defects. These findings will improve our understanding of the maintenance of signal centers and help to elucidate the mechanisms underlying ventral telencephalic patterning.

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Rogers, Nicholas, Dale McAninch, and Paul Thomas. "Dbx1 Is a Direct Target of SOX3 in the Spinal Cord." PLoS ONE 9, no. 4 (April 21, 2014): e95356. http://dx.doi.org/10.1371/journal.pone.0095356.

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Vann, Nikolas C., Francis D. Pham, John A. Hayes, Andrew Kottick, and Christopher A. Del Negro. "Transient Suppression of Dbx1 PreBötzinger Interneurons Disrupts Breathing in Adult Mice." PLOS ONE 11, no. 9 (September 9, 2016): e0162418. http://dx.doi.org/10.1371/journal.pone.0162418.

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Karlen-Amarante, Marlusa, Alyssa Huff, Nathan A. Baertsch, Debora S. A. Colombari, and Jan-Marino Ramirez. "Optogenetic stimulation of Dbx1 neurons promote increase in sympathetic activity in vivo." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.05862.

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6

Bluske, Krista K., and Yasushi Nakagawa. "Role of the homeodomain transcription factor Dbx1 in patterning the developing diencephalon." Developmental Biology 331, no. 2 (July 2009): 524. http://dx.doi.org/10.1016/j.ydbio.2009.05.511.

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7

Arai, Yoko, Andrzej W. Cwetsch, Eva Coppola, Sara Cipriani, Hidenori Nishihara, Hiroaki Kanki, Yoann Saillour, et al. "Evolutionary Gain of Dbx1 Expression Drives Subplate Identity in the Cerebral Cortex." Cell Reports 29, no. 3 (October 2019): 645–58. http://dx.doi.org/10.1016/j.celrep.2019.09.007.

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Puelles, Luis, Loreta Medina, Ugo Borello, Isabel Legaz, Anne Teissier, Alessandra Pierani, and John L. R. Rubenstein. "Radial derivatives of the mouse ventral pallium traced with Dbx1-LacZ reporters." Journal of Chemical Neuroanatomy 75 (September 2016): 2–19. http://dx.doi.org/10.1016/j.jchemneu.2015.10.011.

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9

Gard, Chris, Gloria Gonzalez Curto, Youcef El-Mokhtar Frarma, Elodie Chollet, Nathalie Duval, Valentine Auzié, Frédéric Auradé, et al. "Pax3- and Pax7-mediated Dbx1 regulation orchestrates the patterning of intermediate spinal interneurons." Developmental Biology 432, no. 1 (December 2017): 24–33. http://dx.doi.org/10.1016/j.ydbio.2017.06.014.

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10

Inamata, Y., and R. Shirasaki. "Dbx1 triggers crucial molecular programs required for midline crossing by midbrain commissural axons." Development 141, no. 6 (February 19, 2014): 1260–71. http://dx.doi.org/10.1242/dev.102327.

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11

Sokolowski, Katie, Shigeyuki Esumi, Tsutomu Hirata, Yasmin Kamal, Tuyen Tran, Andrew Lam, Livio Oboti, et al. "Specification of Select Hypothalamic Circuits and Innate Behaviors by the Embryonic Patterning Gene Dbx1." Neuron 86, no. 2 (April 2015): 403–16. http://dx.doi.org/10.1016/j.neuron.2015.03.022.

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12

Kottick, Andrew, Caroline A. Martin, and Christopher A. Del Negro. "Fate mapping neurons and glia derived from Dbx1-expressing progenitors in mouse preBötzinger complex." Physiological Reports 5, no. 11 (June 2017): e13300. http://dx.doi.org/10.14814/phy2.13300.

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13

Bouvier, J., M. Thoby-Brisson, J. Champagnat, A. Pierani, and G. Fortin. "The homeodomain protein Dbx1 specifies a vital population of respiratory interneurons in the mouse." Revue des Maladies Respiratoires 25, no. 9 (November 2008): 1204. http://dx.doi.org/10.1016/s0761-8425(08)75084-8.

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14

Pierani, A., L. Moran-Rivard, M. J. Sunshine, D. R. Littman, M. Goulding, and T. M. Jessell. "Control of Interneuron Fate in the Developing Spinal Cord by the Progenitor Homeodomain Protein Dbx1." Neuron 29, no. 2 (February 2001): 367–84. http://dx.doi.org/10.1016/s0896-6273(01)00212-4.

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15

Langdon, Casey G., Katherine E. Gadek, Matthew R. Garcia, Myron K. Evans, Kristin B. Reed, Madeline Bush, Jason A. Hanna, et al. "Abstract 1667: Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1667. http://dx.doi.org/10.1158/1538-7445.am2022-1667.

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Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children with no improvements in treatment options for RMS patients over the past four decades. Therefore, it is critical to understand the fundamental processes underlying RMS tumorigenesis. RMS is divided into two major histologic subtypes - alveolar and embryonal RMS. Nearly all alveolar RMS express oncogenic fusions of PAX3-FOXO1 or PAX7-FOXO1 whereas embryonal RMS are not driven by these fusion proteins. Instead, embryonal or fusion-negative (FN-RMS) are molecularly heterogeneous. Approximately one-third of fusion-negative RMS (FN-RMS) patients have copy number loss of PTEN (phosphatase and tensin homolog), and approximately 90% of tumors are hypermethylated at the PTEN promoter leading to decreased PTEN expression. This indicates a near universal role for PTEN loss in FN-RMS, but the functional role of PTEN is still unclear. To determine PTEN’s function in FN-RMS, we bred Ptenflox alleles into our aP2-Cre;SmoM2 (ASPWT) FN-RMS mouse model to obtain aP2-Cre;SmoM2;Ptenflox/flox mice (ASPcKO). Conditional Pten deletion accelerated tumorigenesis and produced a tumor with a less differentiated histological appearance, much like human FN-RMS. Interestingly, in PtenWT tumors, we found predominant PTEN immunoreactivity within the nucleus suggesting a role for nuclear PTEN in FN-RMS. Transcriptome analyses revealed robust gene expression changes between the ASPWT and ASPcKO tumors. The top overexpressed gene in ASPcKO tumors was Dbx1 (Developing brain homeobox 1), a homeobox transcription factor with no known cancer function but involved in innate behavioral processes such as breathing. We found FN-RMS patient-derived xenografts are dependent on DBX1 expression, and that DBX1 expression is controlled by PAX7 (Paired Box 7). PAX7 is a transcription factor expressed in satellite cells and maintains a de-differentiated state in FN-RMS. PAX7 expression is also increased in our ASPcKO tumors, and we show that human FN-RMS cells are dependent on PAX7 expression for proliferation. This suggests PTEN loss in FN-RMS engages a new transcriptional program necessary for FN-RMS survival. To determine if Pax7 loss can rescue the deleterious effects of Pten loss in our murine FN-RMS model, we deleted both Pten and Pax7 in our aP2-Cre;SmoM2 mice (ASPcKOP7cKO). ASPcKOP7cKO tumor onset kinetics resembled tumors with wild-type PTEN and were negative for skeletal muscle markers MYOD1 and MYOGENIN. However, these tumors were positive for leiomyosarcoma markers smooth muscle actin and CALDESMON. Together, our data suggests PTEN and PAX7 have a synthetic essential relationship in FN-RMS and that PAX7 is a proliferative driver and lineage dependency for FN-RMS tumors. This work also illustrates the power of murine models to unravel the genetic dependencies underlying both tumor maintenance and identity. Citation Format: Casey G. Langdon, Katherine E. Gadek, Matthew R. Garcia, Myron K. Evans, Kristin B. Reed, Madeline Bush, Jason A. Hanna, Catherine J. Drummond, Matthew C. Maguire, Patrick J. Leavey, David Finkelstein, Hongjian Jin, Patrick A. Schreiner, Jerold E. Rehg, Mark E. Hatley. Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1667.

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16

Vann, Nikolas C., Francis D. Pham, Kaitlyn E. Dorst, and Christopher A. Del Negro. "Dbx1 Pre-Bötzinger Complex Interneurons Comprise the Core Inspiratory Oscillator for Breathing in Unanesthetized Adult Mice." eneuro 5, no. 3 (May 2018): ENEURO.0130–18.2018. http://dx.doi.org/10.1523/eneuro.0130-18.2018.

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17

Causeret, Frédéric, Monica Ensini, Anne Teissier, Nicoletta Kessaris, William D. Richardson, Thibaut Lucas de Couville, and Alessandra Pierani. "Dbx1-Expressing Cells Are Necessary for the Survival of the Mammalian Anterior Neural and Craniofacial Structures." PLoS ONE 6, no. 4 (April 28, 2011): e19367. http://dx.doi.org/10.1371/journal.pone.0019367.

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18

Kottick, Andrew, and Christopher A. Del Negro. "Synaptic Depression Influences Inspiratory–Expiratory Phase Transition in Dbx1 Interneurons of the preBötzinger Complex in Neonatal Mice." Journal of Neuroscience 35, no. 33 (August 19, 2015): 11606–11. http://dx.doi.org/10.1523/jneurosci.0351-15.2015.

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19

Griveau, Amélie, Ugo Borello, Frédéric Causeret, Fadel Tissir, Nicole Boggetto, Sonia Karaz, and Alessandra Pierani. "A Novel Role for Dbx1-Derived Cajal-Retzius Cells in Early Regionalization of the Cerebral Cortical Neuroepithelium." PLoS Biology 8, no. 7 (July 27, 2010): e1000440. http://dx.doi.org/10.1371/journal.pbio.1000440.

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20

Nouri, Navid, and Rajeshwar Awatramani. "A novel floor plate boundary defined by adjacent En1 and Dbx1 microdomains distinguishes midbrain dopamine and hypothalamic neurons." Development 144, no. 5 (February 7, 2017): 916–27. http://dx.doi.org/10.1242/dev.144949.

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21

Ruangkittisakul, Araya, Andrew Kottick, Maria C. D. Picardo, Klaus Ballanyi, and Christopher A. Del Negro. "Identification of the pre-Bötzinger complex inspiratory center in calibrated “sandwich” slices from newborn mice with fluorescent Dbx1 interneurons." Physiological Reports 2, no. 8 (August 2014): e12111. http://dx.doi.org/10.14814/phy2.12111.

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22

Koizumi, Hidehiko, Bryan Mosher, Mohammad F. Tariq, Ruli Zhang, Naohiro Koshiya, and Jeffrey C. Smith. "Voltage-Dependent Rhythmogenic Property of Respiratory Pre-Bötzinger Complex Glutamatergic, Dbx1-Derived, and Somatostatin-Expressing Neuron Populations Revealed by Graded Optogenetic Inhibition." eneuro 3, no. 3 (May 2016): ENEURO.0081–16.2016. http://dx.doi.org/10.1523/eneuro.0081-16.2016.

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23

Matise, M. P., M. Lustig, T. Sakurai, M. Grumet, and A. L. Joyner. "Ventral midline cells are required for the local control of commissural axon guidance in the mouse spinal cord." Development 126, no. 16 (August 15, 1999): 3649–59. http://dx.doi.org/10.1242/dev.126.16.3649.

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Specialized cells at the midline of the central nervous system have been implicated in controlling axon projections in both invertebrates and vertebrates. To address the requirement for ventral midline cells in providing cues to commissural axons in mice, we have analyzed Gli2 mouse mutants, which lack specifically the floor plate and immediately adjacent interneurons. We show that a Dbx1 enhancer drives tau-lacZ expression in a subpopulation of commissural axons and, using a reporter line generated from this construct, as well as DiI tracing, we find that commissural axons projected to the ventral midline in Gli2(−/−) embryos. Netrin1 mRNA expression was detected in Gli2(−/−) embryos and, although much weaker than in wild-type embryos, was found in a dorsally decreasing gradient. This result demonstrates that while the floor plate can serve as a source of long-range cues for C-axons in vitro, it is not required in vivo for the guidance of commissural axons to the ventral midline in the mouse spinal cord. After reaching the ventral midline, most commissural axons remained clustered in Gli2(−/−) embryos, although some were able to extend longitudinally. Interestingly, some of the longitudinally projecting axons in Gli2(−/−) embryos extended caudally and others rostrally at the ventral midline, in contrast to normal embryos in which virtually all commissural axons turn rostrally after crossing the midline. This finding indicates a critical role for ventral midline cells in regulating the rostral polarity choice made by commissural axons after they cross the midline. In addition, we provide evidence that interactions between commissural axons and floor plate cells are required to modulate the localization of Nr-CAM and TAG-1 proteins on axons at the midline. Finally, we show that the floor plate is not required for the early trajectory of motoneurons or axons of the posterior commissure, whose projections are directed away from the ventral midline in both WT and Gli2(−/−) embryos, although they are less well organized in Gli2(−/−)mutants.

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Brunquell, Jessica, Jia Yuan, Aqeela Erwin, Sandy D. Westerheide, and Bin Xue. "DBC1/CCAR2 and CCAR1 Are Largely Disordered Proteins that Have Evolved from One Common Ancestor." BioMed Research International 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/418458.

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Deleted in breast cancer 1 (DBC1, CCAR2, KIAA1967) is a large, predominantly nuclear, multidomain protein that modulates gene expression by inhibiting several epigenetic modifiers, including the deacetylases SIRT1 and HDAC3, and the methyltransferase SUV39H1. DBC1 shares many highly conserved protein domains with its paralog cell cycle and apoptosis regulator 1 (CCAR1, CARP-1). In this study, we examined the full-length sequential and structural properties of DBC1 and CCAR1 from multiple species and correlated these properties with evolution. Our data shows that the conserved domains shared between DBC1 and CCAR1 have similar domain structures, as well as similar patterns of predicted disorder in less-conserved intrinsically disordered regions. Our analysis indicates similarities between DBC1, CCAR1, and the nematode protein lateral signaling target 3 (LST-3), suggesting that DBC1 and CCAR1 may have evolved from LST-3. Our data also suggests that DBC1 emerged later in evolution than CCAR1. DBC1 contains regions that show less conservation across species as compared to the same regions in CCAR1, suggesting a continuously evolving scenario for DBC1. Overall, this study provides insight into the structure and evolution of DBC1 and CCAR1, which may impact future studies on the biological functions of these proteins.

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Chini, Claudia C. S., Carlos Escande, Veronica Nin, and Eduardo N. Chini. "DBC1 (Deleted in Breast Cancer 1) modulates the stability and function of the nuclear receptor Rev-erbα." Biochemical Journal 451, no. 3 (April 12, 2013): 453–61. http://dx.doi.org/10.1042/bj20121085.

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The nuclear receptor Rev-erbα has been implicated as a major regulator of the circadian clock and integrates circadian rhythm and metabolism. Rev-erbα controls circadian oscillations of several clock genes and Rev-erbα protein degradation is important for maintenance of the circadian oscillations and also for adipocyte differentiation. Elucidating the mechanisms that regulate Rev-erbα stability is essential for our understanding of these processes. In the present paper, we report that the protein DBC1 (Deleted in Breast Cancer 1) is a novel regulator of Rev-erbα. Rev-erbα and DBC1 interact in cells and in vivo, and DBC1 modulates the Rev-erbα repressor function. Depletion of DBC1 by siRNA (small interfering RNA) in cells or in DBC1-KO (knockout) mice produced a marked decrease in Rev-erbα protein levels, but not in mRNA levels. In contrast, DBC1 overexpression significantly enhanced Rev-erbα protein stability by preventing its ubiquitination and degradation. The regulation of Rev-erbα protein levels and function by DBC1 depends on both the N-terminal and C-terminal domains of DBC1. More importantly, in cells depleted of DBC1, there was a dramatic decrease in circadian oscillations of both Rev-erbα and BMAL1. In summary, our data identify DBC1 as an important regulator of the circadian receptor Rev-erbα and proposes that Rev-erbα could be involved in mediating some of the physiological effects of DBC1.

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Able, Ashley A., Allison J. Richard, and Jacqueline M. Stephens. "Loss of DBC1 (CCAR2) affects TNFα-induced lipolysis and Glut4 gene expression in murine adipocytes." Journal of Molecular Endocrinology 61, no. 4 (November 2018): 195–205. http://dx.doi.org/10.1530/jme-18-0154.

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STAT5A (signal transducer and activator of transcription 5A) is a transcription factor that plays a role in adipocyte development and function. In this study, we report DBC1 (deleted in breast cancer 1 – also known as CCAR2) as a novel STAT5A-interacting protein. DBC1 has been primarily studied in tumor cells, but there is evidence that loss of this protein may promote metabolic health in mice. Currently, the functions of DBC1 in mature adipocytes are largely unknown. Using immunoprecipitation and immunoblotting techniques, we confirmed that there is an association between endogenous STAT5A and DBC1 proteins under physiological conditions in the adipocyte nucleus that is not dependent upon STAT5A tyrosine phosphorylation. We used siRNA to knockdown DBC1 in 3T3-L1 adipocytes to determine the impact on STAT5A activity, adipocyte gene expression and TNFα (tumor necrosis factor α)-regulated lipolysis. The loss of DBC1 did not affect the expression of several STAT5A target genes including Socs3, Cish, Bcl6, Socs2 and Igf1. However, we did observe decreased levels of TNFα-induced glycerol and free fatty acids released from adipocytes with reduced DBC1 expression. In addition, DBC1-knockdown adipocytes had increased Glut4 expression. In summary, DBC1 can associate with STAT5A in adipocyte nucleus, but it does not appear to impact regulation of STAT5A target genes. Loss of adipocyte DBC1 modestly increases Glut4 gene expression and reduces TNFα-induced lipolysis. These observations are consistent with in vivo observations that show loss of DBC1 promotes metabolic health in mice.

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Moreno-Navarrete, José María, María Moreno, Marta Vidal, Francisco Ortega, Marta Serrano, Gemma Xifra, Wifredo Ricart, and José Manuel Fernández-Real. "Deleted in breast cancer 1 plays a functional role in adipocyte differentiation." American Journal of Physiology-Endocrinology and Metabolism 308, no. 7 (April 1, 2015): E554—E561. http://dx.doi.org/10.1152/ajpendo.00286.2014.

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Genetic deletion of Dbc1 in mice reduced adipose tissue senescence and inflammation while promoting an expansion of this tissue. Here, we aimed to investigate DBC1 mRNA and protein levels in human adipose tissue from subjects with a wide spectrum of fat mass ( cohort 1; n = 105) and insulin resistance ( cohort 2; n = 47); we also investigated the effects of DBC1 knockdown on 3T3-L1 adipocyte differentiation. DBC1 mRNA was relatively abundant in both visceral (VAT) and subcutaneous adipose tissue (SAT) (mainly in the adipocyte fraction), being decreased in adipose tissue from obese compared with lean subjects. In both VAT and SAT, DBC1 mRNA levels were negatively associated with BMI and positively associated with age and the expression of PPARγ, GLUT4, IRS1, lipogenic ( FASN, ACACA), lipid droplet-associated genes ( PLIN1, FSP27, ADRP, and TIP47), and lipolytic ( ABDH5, AKAP, and PRKACA) genes but negatively associated with ADIPOQ in VAT. DBC1 mRNA and protein levels were increased in the early stages of adipocyte differentiation of human and 3T3-L1 adipocytes. Dbc1 knockdown (KD) with lentivirus led to enhanced adipocyte differentiation, increasing intracellular lipid accumulation and adipogenic gene expression. In conclusion, although DBC1 gene expression was reduced in adipose tissue from obese subjects, it was negatively associated with ADIPOQ gene expression in VAT, suggesting that DBC1 might promote visceral adipose tissue dysfunction. In vitro data supported the antiadipogenic effects of DBC1.

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Zhao, Chen, Aili Dai, Ling Chen, Xiaoping Sun, Xin Han, C. Cameron Yin, and M. James You. "Epigenetic Inactivation of DBC1 in Acute Myeloid Leukaemia." Blood 114, no. 22 (November 20, 2009): 4429. http://dx.doi.org/10.1182/blood.v114.22.4429.4429.

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Abstract Abstract 4429 DNA hypermethylation has important implications in the tumorigenesis and prognosis in acute myeloid leukemia (AML). To identify relevant methylated genes in AML, we have compared several expression and methylation profilings. With expression analysis, we identified that TRPC6, DBC1, DCC and SOX9 have decreased expression levels in the most analyzed AML cell lines. Among these candidates, DBC1 (deleted bladder cancer 1), a putative tumor suppressor, drew our attention because it is frequently methylated not only in hematological malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and acute lymphoblastic leukemia, but also in epithelial cancers. DBC1 may play an important role in the regulation of cell growth and programmed cell death. But the mechanisms of transcriptional control and function role in the hematological malignancies, especially on acute myeloid leukemia, are not well known. In this study, we analyzed the DBC1 expression pattern in 9 AML cell lines with RT-PCR analysis. DBC1 mRNA expression was observed in normal bone-marrow but diminished expression in all of 9 AML cell lines. DBC1 methylation was frequently observed in AML cells (9 of 9, 100%) and inversely correlated with DBC1 mRNA expression in a COBRA analysis (Combined Bisulfite Restriction Analysis). We also detected a frequent methylation of DBC1 in primary AML patient samples (9 of 9, 100%). These findings indicate that DBC1 is frequently silenced by hypermethylation in AML. We are in the process of investigation the functional role of DBC1 in the pathogenesis. In addition, diagnostic and prognostic values of DBC1 in AML are being pursued.* Chen Zhao and Aili Dai contributed equally to the presented work. Disclosures: No relevant conflicts of interest to declare.

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Xu, Xiaoqin, Xin Yang, Xue Liu, Yanghui Bi, Pengzhou Kong, Yanqiang Wang, Xiaolong Cheng, and Yanfeng Xi. "The Role of DBR1 as a Candidate Prognosis Biomarker in Esophageal Squamous Cell Carcinoma." Technology in Cancer Research & Treatment 21 (January 2022): 153303382210831. http://dx.doi.org/10.1177/15330338221083105.

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Aims: Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent malignancies with unfavorable clinical outcomes and limited therapeutic methods. As a key enzyme in RNA metabolism, debranching RNA Lariats 1 (DBR1) is involved in intron turnover and biogenesis of noncoding RNA. Although cancer cells often show disorder of nucleic acid metabolism, it is unclear whether DBR1 has any effect on the carcinogenesis and progression of ESCC. Methods: Here we detected DBR1 expression in 112 ESCC samples by immunohistochemistry and analyzed its correlation with clinical parameters and survival. Results: DBR1 is mainly located in the nucleus of ESCC tissue. And DBR1 was associated with several malignant clinical features in patients, including tumor location ( χ2 = 9.687, P = .021), pathologic T stage ( χ2 = 5.771, P = .016), lymph node metastasis ( χ2 = 8.215, P = .004) and N classification ( χ2 = 10.066, P = .018). Moreover, Kaplan-Meier analysis showed that ESCC patients harboring lower DBR1 expression had a worse prognosis in comparison with those with higher DBR1 expression ( P = .005). Univariate and multivariate Cox proportional hazards regression analyses indicated that decreased DBR1 might act as an independent predictor of poor prognosis for ESCC patients. Conclusion: Abnormal RNA metabolism might play a critical role in promoting the progression of ESCC, and DBR1 may be a promising potential biomarker for predicting the prognosis of ESCC patients.

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Xie, Chichu, Fangming Zhu, Julie Wang, Weizhou Zhang, Joseph A. Bellanti, Bin Li, David Brand, Nancy Olsen, and Song Guo Zheng. "Off-Target Deletion of Conditional Dbc1 Allele in the Foxp3YFP-Cre Mouse Line under Specific Setting." Cells 8, no. 11 (October 24, 2019): 1309. http://dx.doi.org/10.3390/cells8111309.

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The Cre-LoxP conditional knockout strategy has been used extensively to study gene function in a specific cell-type. In this study, the authors tried to engineer mice in which the Dbc1 gene is conditionally knocked out in Treg cells. Unexpectedly, the conditional Dbc1 allele was completely deleted with a low frequency in some Foxp3YFP-Cre mice harboring floxed Dbc1 allele under specific settings. It was found that the germline recombination of floxed Dbc1 allele, which caused Dbc1 knock out mice, occurred in the male Foxp3YFP-Cre mice harboring floxed Dbc1 allele. Even though the authors documented that Foxp3 is expressed in the testis, the germline recombination was not caused by the germline expression of Cre, which was driven by the Foxp3 promoter. The germline recombination may be caused by the unspecific expression of Cre recombinase in the fetus, in which the floxed Dbc1 allele of some stem cells with development potential to germ cells may be recombined. Additionally, this study found that the floxed Dbc1 allele was recombined in non-T cells of some Foxp3Cre Dbc1fl mice, which need to be characterized. Our results also suggest that using male mice with a low frequency of recombined gene allele can reduce the risk of having full knock out mice.

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Fang, Deyu. "Deleted in breast cancer 1 (DBC1) is a molecular checkpoint of B cell autoimmunity (BA2P.130)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 45.17. http://dx.doi.org/10.4049/jimmunol.192.supp.45.17.

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Abstract Self-reactive B cells in the periphery are maintained in a tolerized state through low levels of sCD40L and BAFF (B-cell Activating Factor) signaling. Loss of tolerance due to hyperproduction of CD40L or BAFF, or uncontrolled downstream signaling following activation is associated with multiple autoimmune diseases. In this study we identify Deleted in Breast Cancer 1 (DBC1) as a novel suppressor of B cell activation and autoantibody production. Mice with targeted deletion of Dbc1 gene have hyper-responsive B cells, which produce immunoglobulin, in particular IgG and IgA isotypes, against self-antigens when immunized with antigen without adjuvant. At the molecular level, DBC1 suppresses B cell function by regulating alternative NFΚB members RelB and p52 during the early phase of CD40 and BAFFR stimulation. In addition, IKKα regulates DBC1 interaction with RelB:p52 during B cell activation by phosphorylating a serine cluster at the C-terminus of DBC1. Finally, loss of DBC1 results in spontaneous autoantibody in aged mice. This study reveals that DBC1 functions as a critical regulator in the B cell immune tolerance checkpoint by suppressing the alternative NFκB pathway.

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Lim, Wonchung, Moon-Hyon Hwang, Chounghun Kang, So Yeon Kim, and Hyeseong Cho. "Voluntary exercise training improves body weight of leptin-deficient ob/ob mice by altering hepatic stearoyl-CoA desaturase 1 and deleted in breast cancer 1 protein levels." Physical Activity and Nutrition 25, no. 4 (December 31, 2021): 54–58. http://dx.doi.org/10.20463/pan.2021.0026.

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[Purpose] Deleted in breast cancer 1 (DBC1) ablation causes obesity, and stearoyl-CoA desaturase 1 (SCD1) induces the biosynthesis of monounsaturated fatty acids. This study examined whether voluntary wheel running (VWR) alters SCD-1 and DBC1 protein levels in the liver of leptin-deficient ob/ob mice.[Methods] Twenty-five Ob/Ob mice were divided into two groups (ob/ob-Sed and ob/ob-Ex). The expression of DBC1 and SCD1 in the mouse liver was determined using western blotting.[Results] After 10 weeks, VWR significantly reduced body weight without affecting the fatty acid synthase and CD36 protein levels. The average daily running distance was 4.0±1.0 km/day. This improvement was associated with changes in the hepatic SCD1 and DBC1 levels. Hepatic SCD-1 protein levels increased significantly, and DBC1 protein levels decreased in ob/ob-Sed animals. On the other hand, VWR inhibited the obesity-induced increase in SCD1 expression and impaired the obesity-induced decrease in DBC1 expression in the liver of leptin-deficient ob/ob mice.[Conclusion] This is the first study showing that VWR has strong effects on hepatic SCD1 and DBC1 in ob/ob mice, and provides key insights into the effects of exercise on obesity.

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Salem, Laura A., Christopher L. Boucher, and Thomas M. Menees. "Relationship between RNA Lariat Debranching and Ty1 Element Retrotransposition." Journal of Virology 77, no. 23 (December 1, 2003): 12795–806. http://dx.doi.org/10.1128/jvi.77.23.12795-12806.2003.

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ABSTRACT The Saccharomyces cerevisiae DBR1 gene encodes a 2′-5′ phosphodiesterase that debranches intron RNA lariats following splicing. Yeast dbr1 mutants accumulate intron lariats and are also defective for mobility of the retrotransposons Ty1 and Ty3. We used a mutagenic PCR method to generate a collection of dbr1 mutant alleles to explore the relationship between the roles of DBR1 in transposition and debranching. Eight mutants defective for Ty1 transposition contained single amino acid changes in Dbr1p. Two mutations, G84A and N85D, are in a conserved phosphoesterase motif that is believed to be part of the active site of the enzyme, supporting a connection between enzymatic activity and Ty1 transposition. Two other mutations, Y68F and Y68D, occur at a potential phosphorylation site, and we have shown that Dbr1p is phosphorylated on tyrosine. We have developed an RNase protection assay to quantitate intron RNA accumulation in cells. The assay uses RNA probes that hybridize to ACT1 intron RNA. Protection patterns confirm that sequences from the 5′ end of the intron to the lariat branch point accumulate in dbr1 mutants in a branched (lariat) conformation. RNase protection assays indicate that all of the newly generated dbr1 mutant alleles are also deficient for debranching, further supporting a role for 2′-5′ phosphodiesterase activity in Ty1 transposition. A Ty1 element lacking most of its internal sequences transposes independently of DBR1. The existence of Dbr1p-dependent Ty1 sequences raises the possibility that Dbr1p acts on Ty1 RNA.

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Alfarsi, Lutfi H., Rokaya El Ansari, Brendah K. Masisi, Ruth Parks, Omar J. Mohammed, Ian O. Ellis, Emad A. Rakha, and Andrew R. Green. "Integrated Analysis of Key Differentially Expressed Genes Identifies DBN1 as a Predictive Marker of Response to Endocrine Therapy in Luminal Breast Cancer." Cancers 12, no. 6 (June 12, 2020): 1549. http://dx.doi.org/10.3390/cancers12061549.

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Endocrine therapy is the mainstay of adjuvant treatment for patients with luminal breast cancer. Despite ongoing advances in endocrine therapy to date, a proportion of patients ultimately develop endocrine resistance, resulting in failure of therapy and poor prognosis. Therefore, as part of the growing concept of personalised medicine, the need for identification of predictive markers of endocrine therapy response at an early stage, is recognised. The METABRIC series was used to identify differentially expressed genes (DEGs) in term of response to adjuvant endocrine therapy. Drebrin 1 (DBN1) was identified as a key DEG associated with response to hormone treatment. Next, large, well-characterised cohorts of primary luminal breast cancer with long-term follow-up were assessed at the mRNA and protein levels for the value of DBN1 as a prognostic marker in luminal breast cancer, as well as its potential for predicting the benefit of endocrine therapy. DBN1 positivity was associated with aggressive clinicopathological variables and poor patient outcomes. Importantly, high DBN1 expression predicted relapse patients who were subject to adjuvant endocrine treatment. Our results further demonstrate that DBN1 is an independent prognostic marker in luminal breast cancer. Its association with the response to endocrine therapy and outcome provides evidence for DBN1 as a potential biomarker in luminal breast cancer, particularly for the benefit of endocrine treatment. Further functional investigations into the mechanisms underlying sensitivity to endocrine therapy is required.

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Li, Bin, Siyuan Ding, Ningguo Feng, Nancie Mooney, Yaw Shin Ooi, Lili Ren, Jonathan Diep, et al. "Drebrin restricts rotavirus entry by inhibiting dynamin-mediated endocytosis." Proceedings of the National Academy of Sciences 114, no. 18 (April 17, 2017): E3642—E3651. http://dx.doi.org/10.1073/pnas.1619266114.

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Despite the wide administration of several effective vaccines, rotavirus (RV) remains the single most important etiological agent of severe diarrhea in infants and young children worldwide, with an annual mortality of over 200,000 people. RV attachment and internalization into target cells is mediated by its outer capsid protein VP4. To better understand the molecular details of RV entry, we performed tandem affinity purification coupled with high-resolution mass spectrometry to map the host proteins that interact with VP4. We identified an actin-binding protein, drebrin (DBN1), that coprecipitates and colocalizes with VP4 during RV infection. Importantly, blocking DBN1 function by siRNA silencing, CRISPR knockout (KO), or chemical inhibition significantly increased host cell susceptibility to RV infection.Dbn1KO mice exhibited higher incidence of diarrhea and more viral antigen shedding in their stool samples compared with the wild-type littermates. In addition, we found that uptake of other dynamin-dependent cargos, including transferrin, cholera toxin, and multiple viruses, was also enhanced in DBN1-deficient cells. Inhibition of cortactin or dynamin-2 abrogated the increased virus entry observed in DBN1-deficient cells, suggesting that DBN1 suppresses dynamin-mediated endocytosis via interaction with cortactin. Our study unveiled an unexpected role of DBN1 in restricting the entry of RV and other viruses into host cells and more broadly to function as a crucial negative regulator of diverse dynamin-dependent endocytic pathways.

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Gao, Yayi, Jiayou Tang, Weiqian Chen, Qiang Li, Jia Nie, Fang Lin, Qingsi Wu, et al. "Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1." Proceedings of the National Academy of Sciences 112, no. 25 (June 9, 2015): E3246—E3254. http://dx.doi.org/10.1073/pnas.1421463112.

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Forkhead box P3 (FOXP3)-positive Treg cells are crucial for maintaining immune homeostasis. FOXP3 cooperates with its binding partners to elicit Treg cells’ signature and function, but the molecular mechanisms underlying the modulation of the FOXP3 complex remain unclear. Here we report that Deleted in breast cancer 1 (DBC1) is a key subunit of the FOXP3 complex. We found that DBC1 interacts physically with FOXP3, and depletion of DBC1 attenuates FOXP3 degradation in inflammatory conditions. Treg cells from Dbc1-deficient mice were more resistant to inflammation-mediated abrogation of Foxp3 expression and function and delayed the onset and severity of experimental autoimmune encephalomyelitis and colitis in mice. These findings establish a previously unidentified mechanism regulating FOXP3 stability during inflammation and reveal a pathway for potential therapeutic modulation and intervention in inflammatory diseases.

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Kazan, Hasan Hüseyin, Emrah Özcan, Bünyemin Çoşut, Gönül Yenilmez Çiftçi, and Esra Tanrıverdi Eçik. "Novel BODIPY-subphthalocyanine dyads with reasonable photodynamic therapy behaviours." New Journal of Chemistry 44, no. 32 (2020): 13738–44. http://dx.doi.org/10.1039/d0nj02455d.

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In this study, a set of bio-compatible and NIR emissive BODIPY-subphthalocyanine dyads (SP–DBD1–3) that contain amphiphilic triethyleneglycol units supporting partial water solubility and red absorbing BODIPY monomers (DBD1–3) were prepared.

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Alibrahim, Moussa. "Cloud Point Extraction of Direct Blue 71 Dye using Triton X-100 as Nonionic Surfactant." Tenside Surfactants Detergents 58, no. 1 (January 1, 2021): 27–32. http://dx.doi.org/10.1515/tsd-2018-2091.

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Abstract A surfactant-mediated cloud point extraction (CPE) method using the non-ionic surfactant Triton X-100 (TX-100) has been developed to remove the dye Direct Blue 71 (DB71) from a waste water. Most of the dye molecules are solubilized in the coacervate phase so that the dilute phase remains free of the dye. The effects of surfactant concentration, temperature and salt concentration on the different dye concentrations were studied to determine the optimal conditions for removing DB71. The concentration of DB71 in the dilute phase was measured using UV-Vis spectrophotometer. It was found that the separation of phases was complete and the recovery of DB71 was very effective in the presence of NaCl as an electrolyte. The results showed that up to 25 ppm DB71, i.e. more than 95%, can be quantitatively removed by cloud point extraction procedures in a single extraction at optimal conditions. It was also observed that at a dye concentration of 1 ppm, 100% of the blue dye DB71 can be directly removed with a TX-100 concentration of 12% by weight. At higher dye concentrations of up to 30 ppm, 94.7%-100% dye can be removed. The TX-100 concentration was 12 wt%, the salt concentration (NaCl) 0.005 M and the temperature 75°C. It is concluded that the surfactant mediated cloud point extraction method for dye removal can be an alternative to current dye removal methods.

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Gunalan, Karthigayan, Eugenia Lo, Jessica B. Hostetler, Delenasaw Yewhalaw, Jianbing Mu, Daniel E. Neafsey, Guiyun Yan, and Louis H. Miller. "Role ofPlasmodium vivaxDuffy-binding protein 1 in invasion of Duffy-null Africans." Proceedings of the National Academy of Sciences 113, no. 22 (May 17, 2016): 6271–76. http://dx.doi.org/10.1073/pnas.1606113113.

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The ability of the malaria parasitePlasmodium vivaxto invade erythrocytes is dependent on the expression of the Duffy blood group antigen on erythrocytes. Consequently, Africans who are null for the Duffy antigen are not susceptible toP. vivaxinfections. Recently,P. vivaxinfections in Duffy-null Africans have been documented, raising the possibility thatP. vivax, a virulent pathogen in other parts of the world, may expand malarial disease in Africa.P. vivaxbinds the Duffy blood group antigen through its Duffy-binding protein 1 (DBP1). To determine if mutations in DBP1 resulted in the ability ofP. vivaxto bind Duffy-null erythrocytes, we analyzedP. vivaxparasites obtained from two Duffy-null individuals living in Ethiopia where Duffy-null and -positive Africans live side-by-side. We determined that, although the DBP1s from these parasites contained unique sequences, they failed to bind Duffy-null erythrocytes, indicating that mutations in DBP1 did not account for the ability ofP. vivaxto infect Duffy-null Africans. However, an unusual DNA expansion of DBP1 (three and eight copies) in the two Duffy-nullP. vivaxinfections suggests that an expansion of DBP1 may have been selected to allow low-affinity binding to another receptor on Duffy-null erythrocytes. Indeed, we show that Salvador (Sal) IP. vivaxinfects Squirrel monkeys independently of DBP1 binding to Squirrel monkey erythrocytes. We conclude thatP. vivaxSal I and perhapsP. vivaxin Duffy-null patients may have adapted to use new ligand–receptor pairs for invasion.

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Clark, Nathaniel E., Adam Katolik, Kenneth M. Roberts, Alexander B. Taylor, Stephen P. Holloway, Jonathan P. Schuermann, Eric J. Montemayor, et al. "Metal dependence and branched RNA cocrystal structures of the RNA lariat debranching enzyme Dbr1." Proceedings of the National Academy of Sciences 113, no. 51 (December 6, 2016): 14727–32. http://dx.doi.org/10.1073/pnas.1612729114.

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Intron lariats are circular, branched RNAs (bRNAs) produced during pre-mRNA splicing. Their unusual chemical and topological properties arise from branch-point nucleotides harboring vicinal 2′,5′- and 3′,5′-phosphodiester linkages. The 2′,5′-bonds must be hydrolyzed by the RNA debranching enzyme Dbr1 before spliced introns can be degraded or processed into small nucleolar RNA and microRNA derived from intronic RNA. Here, we measure the activity of Dbr1 fromEntamoeba histolyticaby using a synthetic, dark-quenched bRNA substrate that fluoresces upon hydrolysis. Purified enzyme contains nearly stoichiometric equivalents of Fe and Zn per polypeptide and demonstrates turnover rates of ∼3 s−1. Similar rates are observed when apo-Dbr1 is reconstituted with Fe(II)+Zn(II) under aerobic conditions. Under anaerobic conditions, a rate of ∼4.0 s−1is observed when apoenzyme is reconstituted with Fe(II). In contrast, apo-Dbr1 reconstituted with Mn(II) or Fe(II) under aerobic conditions is inactive. Diffraction data from crystals of purified enzyme using X-rays tuned to the Fe absorption edge show Fe partitions primarily to the β-pocket and Zn to the α-pocket. Structures of the catalytic mutant H91A in complex with 7-mer and 16-mer synthetic bRNAs reveal bona fide RNA branchpoints in the Dbr1 active site. A bridging hydroxide is in optimal position for nucleophilic attack of the scissile phosphate. The results clarify uncertainties regarding structure/function relationships in Dbr1 enzymes, and the fluorogenic probe permits high-throughput screening for inhibitors that may hold promise as treatments for retroviral infections and neurodegenerative disease.

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Nam, K., G. Lee, J. Trambley, S. E. Devine, and J. D. Boeke. "Severe growth defect in a Schizosaccharomyces pombe mutant defective in intron lariat degradation." Molecular and Cellular Biology 17, no. 2 (February 1997): 809–18. http://dx.doi.org/10.1128/mcb.17.2.809.

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The cDNAs and genes encoding the intron lariat-debranching enzyme were isolated from the nematode Caenorhabditis elegans and the fission yeast Schizosaccharomyces pombe based on their homology with the Saccharomyces cerevisiae gene. The cDNAs were shown to be functional in an interspecific complementation experiment; they can complement an S. cerevisiae dbr1 null mutant. About 2.5% of budding yeast S. cerevisiae genes have introns, and the accumulation of excised introns in a dbr1 null mutant has little effect on cell growth. In contrast, many S. pombe genes contain introns, and often multiple introns per gene, so that S. pombe is estimated to contain approximately 40 times as many introns as S. cerevisiae. The S. pombe dbr1 gene was disrupted and shown to be nonessential. Like the S. cerevisiae mutant, the S. pombe null mutant accumulated introns to high levels, indicating that intron lariat debranching represents a rate-limiting step in intron degradation in both species. Unlike the S. cerevisiae mutant, the S. pombe dbr1::leu1+ mutant had a severe growth defect and exhibited an aberrant elongated cell shape in addition to an intron accumulation phenotype. The growth defect of the S. pombe dbr1::leu1+ strain suggests that debranching activity is critical for efficient intron RNA degradation and that blocking this pathway interferes with cell growth.

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Gunalan, Karthigayan, Juliana M. Sá, Roberto R. Moraes Barros, Sarah L. Anzick, Ramoncito L. Caleon, J. Patrick Mershon, Kishore Kanakabandi, et al. "Transcriptome profiling ofPlasmodium vivaxinSaimirimonkeys identifies potential ligands for invasion." Proceedings of the National Academy of Sciences 116, no. 14 (March 14, 2019): 7053–61. http://dx.doi.org/10.1073/pnas.1818485116.

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Unlike the case in Asia and Latin America,Plasmodium vivaxinfections are rare in sub-Saharan Africa due to the absence of the Duffy blood group antigen (Duffy antigen), the only known erythrocyte receptor for theP. vivaxmerozoite invasion ligand, Duffy binding protein 1 (DBP1). However,P. vivaxinfections have been documented in Duffy-negative individuals throughout Africa, suggesting thatP. vivaxmay use ligands other than DBP1 to invade Duffy-negative erythrocytes through other receptors. To identify potentialP. vivaxligands, we compared parasite gene expression inSaimiriandAotusmonkey erythrocytes infected withP. vivaxSalvador I (Sal I). DBP1 bindsAotusbut does not bind toSaimirierythrocytes; thus,P. vivaxSal I must invadeSaimirierythrocytes independent of DBP1. Comparing RNA sequencing (RNAseq) data for late-stage infections inSaimiriandAotuserythrocytes when invasion ligands are expressed, we identified genes that belong to tryptophan-rich antigen and merozoite surface protein 3 (MSP3) families that were more abundantly expressed inSaimiriinfections compared withAotusinfections. These genes may encode potential ligands responsible forP. vivaxinfections of Duffy-negative Africans.

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Maloney, Shawn C., Emilia Antecka, Alexandre N. Odashiro, Bruno F. Fernandes, Madeline Doyle, Li-Anne Lim, Yousef Katib, and Miguel N. Burnier. "Expression of SIRT1 and DBC1 in Developing and Adult Retinas." Stem Cells International 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/908183.

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Sirtuin 1 (SIRT1) is a deacetylase that can regulate various biological processes via repression of transcription. Its activity has been linked to the differentiation of neural progenitor cells, although little is known about its function during retinal development. The study described herein was undertaken to evaluate the expression of SIRT1 and its innate inhibitor, DBC1, in retinal tissues and progenitor cells. We found both SIRT1 and DBC1 to be widely expressed in mouse and human retinas, with subtle differences in subcellular distribution of each protein. We further demonstrate that nuclear-localized SIRT1 is only seen in human-derived retinal progenitor cells and not in adult retinas, suggesting that this nuclear localization may be important in retinal development. Moreover, we observed cytoplasmic DBC1 in a subset of progenitor cells as well as in mature ganglion cells, indicating that the progenitor cell subset, which was comprised predominantly of small cells, may represent a population of ganglion cell precursors. Collectively, the data presented in this study provide support for SIRT1 and DBC1 as regulators of retinal development and normal retinal physiology.

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Basu, Subham, Mahesh Barad, Dipika Yadav, Arijit Nandy, Bidisha Mukherjee, Jit Sarkar, Partha Chakrabarti, Satinath Mukhopadhyay, and Debabrata Biswas. "DBC1, p300, HDAC3, and Siah1 coordinately regulate ELL stability and function for expression of its target genes." Proceedings of the National Academy of Sciences 117, no. 12 (March 9, 2020): 6509–20. http://dx.doi.org/10.1073/pnas.1912375117.

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Among all of the Super Elongation Complex (SEC) components, ELL1 (also known as ELL) is the only bona fide elongation factor that directly stimulates transcription elongation by RNA polymerase II. However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its stabilization, is completely unknown. Here, we report a function of human DBC1 in regulating ELL stability involving HDAC3, p300, and Siah1. Mechanistically, we show that p300-mediated site-specific acetylation increases, whereas HDAC3-mediated deacetylation decreases, ELL stability through polyubiquitylation by the E3 ubiquitin ligase Siah1. DBC1 competes with HDAC3 for the same binding sites on ELL and thus increases its acetylation and stability. Knockdown of DBC1 reduces ELL levels and expression of a significant number of genes, including those involved in glucose metabolism. Consistently, Type 2 diabetes patient-derived peripheral blood mononuclear cells show reduced expression of DBC1 and ELL and associated key target genes required for glucose homeostasis. Thus, we describe a pathway of regulating stability and functions of key elongation factor ELL for expression of diverse sets of genes, including ones that are linked to Type 2 diabetes pathogenesis.

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Espinoza, Isabel, Christian Sandoval-Pauker, Guerrero Ramos, Jentzsch Vargas, and Bisesti Muñoz. "Fenton process combined with precipitation for the removal of Direct Blue 1 dye: A new approach." Journal of the Serbian Chemical Society 85, no. 4 (2020): 547–58. http://dx.doi.org/10.2298/jsc190804119e.

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Azo dyes are recalcitrant pollutants present in effluents of several industries. Due to their chemical stability, their degradation efficiency is not satisfactory by conventional technologies. Advanced oxidation processes, such as Fenton, can be applied for the removal of recalcitrant compounds. However, these methods are still costly. In this work, Fenton and precipitation treatments were combined for the removal (i.e., decolorization) of direct blue 1 (DB1), as an option to decrease operational costs. The individual treatments were studied separately using DB1 solutions 0.04 mmol L-1 to determine the effects of the parameters involved in each process. For the Fenton treatment, the c(Fe2+):c(H2O2) ratio that allowed the highest DB1 decolorization was 1:40. Regarding precipitation, the highest dye decolorization was achieved at a pH value of 6.0. Moreover, it was determined that a minimum c(DB1):c(Fe2+) ratio of 1:7.7 is needed to allow the decolorization of the dye by precipitation. Fenton assisted with precipitation tests were performed with DB1 solutions 0.09 mmol L-1 and using a c(DB1):c(Fe2+) ratio of 1:7.3 (which allows only partial precipitation of DB1). The results suggested that the dye can be treated by a Fenton process for 5 min and then precipitated to achieve the almost total decolorization of the dye (97.79 %). Azo dyes are recalcitrant pollutants present in effluents of several industries. Due to their chemical stability, their degradation efficiency is not satisfactory by conventional technologies. Advanced oxidation processes, such as Fenton, can be applied for the removal of recalcitrant compounds. However, these methods are still costly. In this work, Fenton and precipitation treatments were combined for the removal (i.e., decolorization) of direct blue 1 (DB1), as an option to decrease operational costs. The individual treatments were studied separately using DB1 solutions 0.04 mmol L-1 to determine the effects of the parameters involved in each process. For the Fenton treatment, the c(Fe2+):c(H2O2) ratio that allowed the highest DB1 decolorization was 1:40. Regarding precipitation, the highest dye decolorization was achieved at a pH value of 6.0. Moreover, it was determined that a minimum c(DB1):c(Fe2+) ratio of 1:7.7 is needed to allow the decolorization of the dye by precipitation. Fenton assisted with precipitation tests were performed with DB1 solutions 0.09 mmol L-1 and using a c(DB1):c(Fe2+) ratio of 1:7.3 (which allows only partial precipitation of DB1). The results suggested that the dye can be treated by a Fenton process for 5 min and then precipitated to achieve the almost total decolorization of the dye (97.79 %).

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Cui, Feng, Xueying Han, Xiaoqian Zhang, Siqi Wang, Na Liang, Qing Tan, Wuga Sha, and Jun Li. "ML216 Prevents DNA Damage-Induced Senescence by Modulating DBC1–BLM Interaction." Cells 12, no. 1 (December 29, 2022): 145. http://dx.doi.org/10.3390/cells12010145.

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DNA damage is the major cause of senescence and apoptosis; however, the manner by which DNA-damaged cells become senescent remains unclear. We demonstrate that DNA damage leads to a greater level of senescence rather than apoptosis in DBC1-deficient cells. In addition, we show that BLM becomes degraded during DNA damage, which induces p21 expression and senescence. DBC1 binds to and shields BLM from degradation, thus suppressing senescence. ML216 promotes DBC1–BLM interaction, which aids in the preservation of BLM following DNA damage and suppresses senescence. ML216 enhances pulmonary function by lowering the levels of senescence and fibrosis in both aged mice and a mouse model of bleomycin-induced idiopathic pulmonary fibrosis. Our data reveal a unique mechanism preventing DNA-damaged cells from becoming senescent, which may be regulated by the use of ML216 as a potential treatment for senescence-related diseases.

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Smarzewski, Piotr. "Analysis of Failure Mechanics in Hybrid Fibre-Reinforced High-Performance Concrete Deep Beams with and without Openings." Materials 12, no. 1 (December 29, 2018): 101. http://dx.doi.org/10.3390/ma12010101.

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The article presents the results of experimental- and analytical investigations of the behaviour and the load-carrying capacity of deep beams with openings (DBO) and without openings (DB) made of hybrid steel-polypropylene fibre-reinforced high-performance concrete (HFRHPC) subjected to three-point bending tests. Six deep beams 100 mm × 500 mm × 1000 mm were tested with a gradually increasing load until failure. All the specimens were tested in the same simply supported conditions. The research focused on the quantity and kind of concrete reinforcement. The deep beams with steel and polypropylene (PP) fibres were characterised by variously arranged steel bar reinforcement: vertically, horizontally, orthogonally and diagonally. The DB1, DBO1 deep beams were conventionally made with steel rod reinforcement but without fibres. The steel wire mesh reinforcement was replaced by fibre reinforcement of varying volume percentages in the remaining deep beams. The influence of the hybrid fibre content in the specimens was studied by marking the development and propagation of cracks, by recording the failure modes, and by monitoring the deflections at the bottom of the deep beam, at the mid-span and at the support. Three-dimensional measurements of strain and displacement of the deep beams without openings (DB) were performed by the non-contact optical 3D deformation measuring system ARAMIS. The experimental results were compared with the studied methods of predicting the shear strength of deep beams reinforced with hybrid fibre. The conducted study demonstrates that hybrid fibres as web reinforcement have a favourable impact on deep beam crack widths and raise the load carrying capacity of deep beams with openings.

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Zhang, Yansheng, Keat H. Teoh, Darwin W. Reed, and Patrick S. Covello. "Molecular cloning and characterization of Dbr1, a 2-alkenal reductase from Artemisia annuaThe nucleotide sequence reported in this article has been deposited in the GenBank database under accession No. FJ750460.This paper is one of a selection of papers published in a Special Issue from the National Research Council of Canada – Plant Biotechnology Institute." Botany 87, no. 6 (June 2009): 643–49. http://dx.doi.org/10.1139/b09-033.

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The molecular genetics of carbon–carbon double bond reduction in the plant Artemisia annua L. was studied. Expressed sequence tags from this plant were investigated for sequences with similarity to known double-bond reductases. This resulted in the isolation of a cDNA, corresponding to the gene A. annua Dbr1 (Double bond reductase1), encoding a member of the medium chain dehydrogenase/reductase protein superfamily with sequence similarity to tobacco allyl alcohol dehydrogenase. Recombinant A. annua Dbr1 protein was purified from Escherischia coli and shown to catalyze the reduction of the carbon–carbon double bond of 2-alkenals. This activity included the reduction of the double bond at C11–C13 in the artemisinin precursor artemisinic aldehyde, albeit with unnatural stereochemistry. The substrate specificity, product stereochemistry, and expression pattern of A. annua Dbr1 point to its involvement in planta in the detoxification of 2-alkenals, which may be generated under oxidative stress conditions.

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Leucht, S. "DB01-02 - Polypharmacy should be avoided." European Psychiatry 27 (January 2012): 1. http://dx.doi.org/10.1016/s0924-9338(12)74084-1.

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Menees, Thomas M. "RNA Lariat Debranching Enzyme as a Retroviral and Long-Terminal-Repeat Retrotransposon Host Factor." Annual Review of Virology 7, no. 1 (September 29, 2020): 189–202. http://dx.doi.org/10.1146/annurev-virology-012720-094902.

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Host cell factors are integral to viral replication. Human immunodeficiency virus 1 (HIV-1), the retroviral agent of acquired immune deficiency syndrome, requires several host factors for reverse transcription of the viral genomic RNA (gRNA) into DNA shortly after viral entry. One of these host factors is the RNA lariat debranching enzyme (Dbr1), which cleaves the 2′–5′ bond of branched and lariat RNAs. A recent study has revealed that Dbr1 cleaves HIV-1 gRNA lariats that form early after viral entry. Without Dbr1 activity, HIV-1 reverse transcription stalls, consistent with blockage of viral reverse transcriptase at gRNA branch points. These findings echo an earlier study with the long-terminal-repeat retrotransposon of Saccharomyces cerevisiae, Ty1, which is a retrovirus model. Currently, branching and debranching of viral gRNA are not widely recognized as features of HIV-1 replication, and the role of a gRNA lariat is not known. Future studies will determine whether these gRNA dynamics represent fundamental features of retroviral biology and whether they occur for other positive-sense RNA viruses.

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Journal articles on the topic 'Dbx1'

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