scholarly journals Identification and characterization of a transporter complex responsible for the cytosolic entry of nitrogen-containing-bisphosphonates

2018 ◽  
Author(s):  
Zhou Yu ◽  
Lauren E. Surface ◽  
Chong Yon Park ◽  
Max A. Horlbeck ◽  
Gregory A. Wyant ◽  
...  
Keyword(s):  
Mevalonate Pathway ◽  
Fluid Phase ◽  
Molecular Target ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Genome Wide ◽  
Fluid Phase Endocytosis ◽  
Solute Carrier ◽  
Identification And Characterization

AbstractNitrogen-containing-bisphosphonates (N-BPs) are a class of drugs widely prescribed to treat osteoporosis and other bone-related diseases. Although previous studies have established that N-BPs function by inhibiting the mevalonate pathway in osteoclasts, the mechanism by which N-BPs enter the cytosol from the extracellular space to reach their molecular target is not understood. Here we implemented a CRISPRi-mediated genome-wide screen and identified SLC37A3 (solute carrier family 37 member A3) as a gene required for the action of N-BPs. We observed that SLC37A3 forms a complex with ATRAID (all-trans retinoic acid-induced differentiation factor), a previously identified genetic target of N-BPs. SLC37A3 and ATRAID localize to lysosomes and are required for releasing N-BP molecules that have trafficked to lysosomes through fluid-phase endocytosis into the cytosol. Our results elucidate the route by which N-BPs are delivered to their molecular target, addressing a key aspect of the mechanism of action of N-BPs that may have significant clinical relevance.

scholarly journals Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Zhou Yu ◽  
Lauren E Surface ◽  
Chong Yon Park ◽  
Max A Horlbeck ◽  
Gregory A Wyant ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Mevalonate Pathway ◽  
Fluid Phase ◽  
Molecular Target ◽  
Solute Carrier Family ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Genome Wide ◽  
Fluid Phase Endocytosis ◽  
Solute Carrier

Nitrogen-containing-bisphosphonates (N-BPs) are a class of drugs widely prescribed to treat osteoporosis and other bone-related diseases. Although previous studies have established that N-BPs function by inhibiting the mevalonate pathway in osteoclasts, the mechanism by which N-BPs enter the cytosol from the extracellular space to reach their molecular target is not understood. Here, we implemented a CRISPRi-mediated genome-wide screen and identified SLC37A3 (solute carrier family 37 member A3) as a gene required for the action of N-BPs in mammalian cells. We observed that SLC37A3 forms a complex with ATRAID (all-trans retinoic acid-induced differentiation factor), a previously identified genetic target of N-BPs. SLC37A3 and ATRAID localize to lysosomes and are required for releasing N-BP molecules that have trafficked to lysosomes through fluid-phase endocytosis into the cytosol. Our results elucidate the route by which N-BPs are delivered to their molecular target, addressing a key aspect of the mechanism of action of N-BPs that may have significant clinical relevance.

Presenting White Blood Cell Count and Kinetics of Molecular Remission Predict Prognosis in Acute Promyelocytic Leukemia Treated With All-Trans Retinoic Acid: Result of the Randomized MRC Trial

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4131-4143 ◽  
Author(s):  
Alan K. Burnett ◽  
David Grimwade ◽  
Ellen Solomon ◽  
Keith Wheatley ◽  
Anthony H. Goldstone
Keyword(s):  
Retinoic Acid ◽  
Promyelocytic Leukemia ◽  
Rt Pcr ◽  
Blood Cell Count ◽  
Relapse Risk ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
To Receive ◽  
Risk Of Relapse

Abstract All-trans retinoic acid (ATRA) is an essential component of the treatment of acute promyelocytic leukemia (APL), but the optimal timing and duration remain to be determined. Molecular characterization of this disease can refine the diagnosis and could be potentially useful in monitoring response to treatment. Patients defined morphologically to have APL were randomized to receive a 5-day course of ATRA before commencing chemotherapy or to receive daily ATRA commencing with chemotherapy and continuing until complete remission (CR). The chemotherapy was that used in current MRC Leukaemia Trials. Outcome comparisons were by intention to treat with additional analysis for relevant risk factors. Patients were characterized by molecular techniques for the fusion products of the t(15;17) and monitored by reverse transcriptase-polymerase chain reaction (RT-PCR) during and after treatment. Two hundred thirty-nine patients were randomized. Treatment with extended ATRA resulted in a superior remission rate (87% v 70%, P < .001), due to fewer early and induction deaths (12% v 23%, P = .02), and less resistant disease (2% v 7%, P = .03), which was associated with a significantly more rapid recovery of neutrophils and platelets. Extended ATRA reduced relapse risk (20%v 36% at 4 years, P = .04) and resulted in superior survival (71% v 52% at 4 years, P = .005). Presenting white blood cell count (WBC) was a key determinant of outcome. The 70% of patients who presented with a WBC less than 10 × 109/L had a better CR (85% v62%, P = .0001) and reduced relapse risk (22% v42%, P = .002) and superior survival (69%v 43%, P < .0001). Within the low count group, extended ATRA resulted in a better CR (94% v 76%, P= .001), reduced relapse risk (13% v 35%, P = .04), and improved survival (80% v 57%, P = .0009). There was no evidence of benefit in patients presenting with a higher WBC (>10 × 109/L). Molecular monitoring after the third chemotherapy course had a correlation with risk of relapse. The relapse risk was 57% if the RT-PCR was positive versus 27% if the RT-PCR was negative (P = .006). APL patients who present with a low WBC derive substantial benefit from combining ATRA with induction chemotherapy until remission is achieved, whereas patients with a higher WBC did not benefit. Molecular characterization of disease can improve diagnostic precision and a positive RT-PCR after consolidation identifies patients at a higher risk of relapse.

Genome wide identification and characterization of abiotic stress responsive lncRNAs in Capsicum annuum

2021 ◽  
Author(s):  
Pooja Moni Baruah ◽  
Debasish B. Krishnatreya ◽  
Kuntala Sarma Bordoloi ◽  
Sarvajeet Singh Gill ◽  
Niraj Agarwala
Keyword(s):  
Abiotic Stress ◽  
Capsicum Annuum ◽  
Genome Wide ◽  
Identification And Characterization

scholarly journals Genome wide identification and characterization of light-harvesting Chloro a/b binding (LHC) genes reveals their potential role in enhancing drought tolerance in Gossypium hirsutum

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Teame Gereziher MEHARI ◽  
Yanchao XU ◽  
Richard Odongo MAGWANGA ◽  
Muhammad Jawad UMER ◽  
Joy Nyangasi KIRUNGU ◽  
...  
Keyword(s):  
Drought Stress ◽  
Gossypium Hirsutum ◽  
Abiotic Stresses ◽  
Substitution Rate ◽  
Synonymous Substitution ◽  
Synonymous Substitution Rate ◽  
Drought Tolerant ◽  
Genome Wide ◽  
Identification And Characterization

Abstract Background Cotton is an important commercial crop for being a valuable source of natural fiber. Its production has undergone a sharp decline because of abiotic stresses, etc. Drought is one of the major abiotic stress causing significant yield losses in cotton. However, plants have evolved self-defense mechanisms to cope abiotic factors like drought, salt, cold, etc. The evolution of stress responsive transcription factors such as the trihelix, a nodule-inception-like protein (NLP), and the late embryogenesis abundant proteins have shown positive response in the resistance improvement to several abiotic stresses. Results Genome wide identification and characterization of the effects of Light-Harvesting Chloro a/b binding (LHC) genes were carried out in cotton under drought stress conditions. A hundred and nine proteins encoded by the LHC genes were found in the cotton genome, with 55, 27, and 27 genes found to be distributed in Gossypium hirsutum, G. arboreum, and G. raimondii, respectively. The proteins encoded by the genes were unevenly distributed on various chromosomes. The Ka/Ks (Non-synonymous substitution rate/Synonymous substitution rate) values were less than one, an indication of negative selection of the gene family. Differential expressions of genes showed that majority of the genes are being highly upregulated in the roots as compared with leaves and stem tissues. Most genes were found to be highly expressed in MR-85, a relative drought tolerant germplasm. Conclusion The results provide proofs of the possible role of the LHC genes in improving drought stress tolerance, and can be explored by cotton breeders in releasing a more drought tolerant cotton varieties.

scholarly journals Genome-Wide Identification and Characterization of Hsf and Hsp Gene Families and Gene Expression Analysis under Heat Stress in Eggplant (Solanum melongema L.)

Horticulturae ◽  
2021 ◽  
Vol 7 (6) ◽  
pp. 149
Author(s):  
Chao Gong ◽  
Qiangqiang Pang ◽  
Zhiliang Li ◽  
Zhenxing Li ◽  
Riyuan Chen ◽  
...  
Keyword(s):  
Heat Stress ◽  
Gene Families ◽  
High Temperature Stress ◽  
Pcr Analysis ◽  
Rna Seq ◽  
Genome Wide ◽  
Motif Composition ◽  
Hsp Genes ◽  
Identification And Characterization

Under high temperature stress, a large number of proteins in plant cells will be denatured and inactivated. Meanwhile Hsfs and Hsps will be quickly induced to remove denatured proteins, so as to avoid programmed cell death, thus enhancing the thermotolerance of plants. Here, a comprehensive identification and analysis of the Hsf and Hsp gene families in eggplant under heat stress was performed. A total of 24 Hsf-like genes and 117 Hsp-like genes were identified from the eggplant genome using the interolog from Arabidopsis. The gene structure and motif composition of Hsf and Hsp genes were relatively conserved in each subfamily in eggplant. RNA-seq data and qRT-PCR analysis showed that the expressions of most eggplant Hsf and Hsp genes were increased upon exposure to heat stress, especially in thermotolerant line. The comprehensive analysis indicated that different sets of SmHsps genes were involved downstream of particular SmHsfs genes. These results provided a basis for revealing the roles of SmHsps and SmHsp for thermotolerance in eggplant, which may potentially be useful for understanding the thermotolerance mechanism involving SmHsps and SmHsp in eggplant.

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