Abstract：
:Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age, and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the SIX6 risk variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene, p16INK4a (cyclin-dependent kinase inhibitor 2A, isoform INK4a). We further show that the upregulation of homozygous SIX6 risk alleles (CC) leads to an increase in p16INK4a expression, with subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that SIX6 and/or IOP promotes POAG by directly increasing p16INK4a expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis.
journal_name
Mol Celljournal_title
Molecular cellauthors
Skowronska-Krawczyk D,Zhao L,Zhu J,Weinreb RN,Cao G,Luo J,Flagg K,Patel S,Wen C,Krupa M,Luo H,Ouyang H,Lin D,Wang W,Li G,Xu Y,Li O,Chung C,Yeh E,Jafari M,Ai M,Zhong Z,Shi W,Zheng L,Krawczyk M,Chen D,Shdoi
10.1016/j.molcel.2015.07.027subject
Has Abstractpub_date
2015-09-17 00:00:00pages
931-40issue
6eissn
1097-2765issn
1097-4164pii
S1097-2765(15)00585-7journal_volume
59pub_type
杂志文章相关文献
MOLECULAR CELL文献大全abstract：:The WTX gene is frequently lost or mutated in Wilms tumor. In this issue of Molecular Cell, Kim et al. (2012) identify WTX modulation of p53 tumor-suppressor activity through regulation of p53 acetylation. Therefore, WTX differentially regulates the oncogenic β-catenin pathway and the tumor-suppressing p53 pathway. ...
journal_title：Molecular cell
pub_type： 评论,杂志文章
doi：10.1016/j.molcel.2012.02.010
更新日期：2012-03-09 00:00:00
abstract：:A kinase-anchoring proteins (AKAPs) target PKA to specific microdomains by using an amphipathic helix that docks to N-terminal dimerization and docking (D/D) domains of PKA regulatory (R) subunits. To understand specificity, we solved the crystal structure of the helical motif from D-AKAP2, a dual-specific AKAP, bound...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2006.09.015
更新日期：2006-11-03 00:00:00
abstract：:Protein phase separation by low-complexity, intrinsically disordered domains generates membraneless organelles and links to neurodegeneration. Cellular prion protein (PrPC) contains such domains, causes spongiform degeneration, and is a receptor for Alzheimer's amyloid-β oligomers (Aβo). Here, we show that PrPC separa...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2018.10.009
更新日期：2018-11-01 00:00:00
abstract：:All nuclear transcription is interrupted during mitosis. We examined the role of human TTF2, an RNA polymerase (Pol) I and II termination factor, in mitotic repression of transcription elongation. We find that TTF2 levels rise in the cytoplasm in S and G2 and at the onset of mitosis TTF2 translocates into the nucleus....
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/s1097-2765(04)00234-5
更新日期：2004-05-07 00:00:00
abstract：:CRISPR-Cas12a (Cpf1) is an RNA-guided DNA-cutting nuclease that has been repurposed for genome editing. Upon target DNA binding, Cas12a cleaves both the target DNA in cis and non-target single-stranded DNAs (ssDNAs) in trans. To elucidate the molecular basis for both DNase cleavage modes, we performed structural and b...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2018.11.021
更新日期：2019-02-07 00:00:00
abstract：:A major unresolved question in messenger RNA translation is how ribosomal release factors terminate protein synthesis. Class 1 release factors decode stop codons and trigger hydrolysis of the bond between the nascent polypeptide and tRNA some 75 A away from the decoding site. While the gross features of the release fa...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2007.06.032
更新日期：2007-09-07 00:00:00
abstract：:Nonsense-mediated decay (NMD) is a surveillance system that degrades mRNAs containing a premature termination codon (PTC) and plays important roles in protein homeostasis and disease. The efficiency of NMD is variable, impacting the clinical outcome of genetic mutations. However, limited resolution of bulk analyses ha...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2019.05.008
更新日期：2019-07-25 00:00:00
abstract：:Siz1 is a founding member of the Siz/PIAS RING family of SUMO E3 ligases. The X-ray structure of an active Siz1 ligase revealed an elongated tripartite architecture comprised of an N-terminal PINIT domain, a central zinc-containing RING-like SP-RING domain, and a C-terminal domain we term the SP-CTD. Structure-based m...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2009.07.013
更新日期：2009-09-11 00:00:00
abstract：:Multi-subunit SMC ATPases control chromosome superstructure and DNA topology, presumably by DNA translocation and loop extrusion. Chromosomal DNA is entrapped within the tripartite SMCkleisin ring. Juxtaposed SMC heads ("J heads") or engaged SMC heads ("E heads") split the SMCkleisin ring into "S" and "K" sub-compartm...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2019.05.001
更新日期：2019-07-25 00:00:00
abstract：:Cardiac disease remains the leading cause of morbidity and mortality worldwide. The β1-adrenergic receptor (β1-AR) is a major regulator of cardiac functions and is downregulated in the majority of heart failure cases. A key physiological process is the activation of heterotrimeric G-protein Gs by β1-ARs, leading to in...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2020.08.001
更新日期：2020-10-01 00:00:00
abstract：:Multisite phosphorylation of kinases can induce on-off or graded regulation of catalytic activity; however, its influence on substrate specificity remains unclear. Here, we show that multisite phosphorylation of ribosomal protein S6 kinase 1 (S6K1) alters target selection. Agonist-inducible phosphorylation of glutamyl...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2018.11.017
更新日期：2019-02-07 00:00:00
abstract：:Gene-targeted knockout mice have been generated lacking the major uracil-DNA glycosylase, UNG. In contrast to ung- mutants of bacteria and yeast, such mice do not exhibit a greatly increased spontaneous mutation frequency. However, there is only slow removal of uracil from misincorporated dUMP in isolated ung-/- nucle...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/s1097-2765(00)80271-3
更新日期：2000-06-01 00:00:00
abstract：:XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective XPG mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss resul...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2015.12.026
更新日期：2016-02-18 00:00:00
abstract：:We used computational algorithms to find conserved sequences in the 3' untranslated region (UTR) of transcripts that exhibited rapid decay in primary human T cells and found that the consensus sequence UGUUUGUUUGU, which we have termed a GU-rich element (GRE), was enriched in short-lived transcripts. Using a tet-off r...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2007.11.024
更新日期：2008-02-01 00:00:00
abstract：:RNA sequence motifs are not sufficient for association with RBPs. In this issue of Molecular Cell, Taliaferro et al. (2016) demonstrate that, other than sequence motif, RNA secondary structure plays a repressive role on RBP binding, both in vitro and in vivo. ...
journal_title：Molecular cell
pub_type： 评论,杂志文章
doi：10.1016/j.molcel.2016.10.006
更新日期：2016-10-20 00:00:00
abstract：:Herpes simplex virus (HSV) infection requires binding of the viral envelope glycoprotein D (gD) to cell surface receptors. We report the X-ray structures of a soluble, truncated ectodomain of gD both alone and in complex with the ectodomain of its cellular receptor HveA. Two bound anions suggest possible binding sites...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/s1097-2765(01)00298-2
更新日期：2001-07-01 00:00:00
abstract：:Heterochromatin is refractory to DNA transactions, including repair. In a recent issue of Molecular Cell, Goodarzi et al. (2008) reveal how the central transducing kinase of the DNA damage response relieves this natural barrier by increasing heterochromatic DNA accessibility. ...
journal_title：Molecular cell
pub_type： 评论,杂志文章
doi：10.1016/j.molcel.2008.07.004
更新日期：2008-08-08 00:00:00
abstract：:Vascular endothelial (VE)-cadherin homophilic adhesion controls endothelial barrier permeability through assembly of adherens junctions (AJs). We observed that loss of VE-cadherin-mediated adhesion induced the activation of Src and phospholipase C (PLC)γ2, which mediated Ca(2+) release from endoplasmic reticulum (ER) ...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2012.10.011
更新日期：2012-12-28 00:00:00
abstract：:Maintaining a fluid bilayer is essential for cell signaling and survival. Lipid saturation is a key factor determining lipid packing and membrane fluidity, and it must be tightly controlled to guarantee organelle function and identity. A dedicated eukaryotic mechanism of lipid saturation sensing, however, remains elus...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2016.05.015
更新日期：2016-07-07 00:00:00
abstract：:Repetitive DNA elements are essential for genome function; in this issue of Molecular Cell, Ishak et al. (2016) describe a novel mechanism of epigenetic repression at these elements that requires pRB-dependent recruitment of EZH2. ...
journal_title：Molecular cell
pub_type： 评论,杂志文章
doi：10.1016/j.molcel.2016.11.035
更新日期：2016-12-15 00:00:00
abstract：:Physical and genetic studies verify that the DNA binding domain of protein gpNu1 (which initiates packaging of phage lambda DNA) is a winged helix-turn-helix (w HTH) and that gpNu1 dimers bind sites that are brought close through DNA bending. ...
journal_title：Molecular cell
pub_type： 评论,杂志文章
doi：10.1016/s1097-2765(02)00536-1
更新日期：2002-05-01 00:00:00
abstract：:Floral transition in plants is regulated by an integrated network of flowering genetic pathways. We show that an Arabidopsis PIN1-type parvulin 1, Pin1At, controls floral transition by accelerating cis/trans isomerization of the phosphorylated Ser/Thr-Pro motifs in two MADS-domain transcription factors, SUPPRESSOR OF ...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2009.12.020
更新日期：2010-01-15 00:00:00
abstract：:Innate immune responses are critical for the immediate protection against microbial infection. In Drosophila, infection leads to the rapid and robust production of antimicrobial peptides through two NF-kappaB signaling pathways-IMD and Toll. The IMD pathway is triggered by DAP-type peptidoglycan, common to most Gram-n...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2009.12.036
更新日期：2010-01-29 00:00:00
abstract：:An exciting study in this issue reveals how binding of the microtubule associated protein TPX2 to the mitotic kinase Aurora A induces a conformational change. This moves the phosphorylated activation domain into a more compact position within the kinase core, providing a better substrate binding platform and hiding th...
journal_title：Molecular cell
pub_type： 评论,杂志文章,评审
doi：10.1016/s1097-2765(03)00405-2
更新日期：2003-10-01 00:00:00
abstract：:Cells constantly adjust their metabolism in response to environmental conditions, yet major mechanisms underlying survival remain poorly understood. We discover a posttranscriptional mechanism that integrates starvation response with GTP homeostasis to allow survival, enacted by the nucleotide (p)ppGpp, a key player i...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2012.08.009
更新日期：2012-10-26 00:00:00
abstract：:MYOD-directed fibroblast trans-differentiation into skeletal muscle provides a unique model to investigate how one transcription factor (TF) reconfigures the three-dimensional chromatin architecture to control gene expression, which is otherwise achieved by the combinatorial activities of multiple TFs. Integrative ana...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2019.07.036
更新日期：2019-11-07 00:00:00
abstract：:Autophagy is required for benign hepatic tumors to progress into malignant hepatocellular carcinoma. However, the mechanism is unclear. Here, we report that mitophagy, the selective removal of mitochondria by autophagy, positively regulates hepatic cancer stem cells (CSCs) by suppressing the tumor suppressor p53. When...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2017.09.022
更新日期：2017-10-19 00:00:00
abstract：:Transcription is repressed if a DNA double-strand break (DSB) is introduced in close proximity to a transcriptional activation site at least in part by H2A-ubiquitination. While ATM signaling is involved, how it controls H2A-ubiquitination remains unclear. Here, we identify that, in response to DSBs, a transcriptional...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2015.03.023
更新日期：2015-05-07 00:00:00
abstract：:Bicoid (BCD), the anterior determinant of Drosophila, controls embryonic gene expression by transcriptional activation and translational repression. Both functions require the homeodomain (HD), which recognizes DNA motifs at target gene enhancers and a specific sequence interval in the 3' untranslated region of caudal...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/s1097-2765(00)80434-7
更新日期：2000-02-01 00:00:00
abstract：:Anti-sense transcription originating upstream of mammalian protein-coding genes is a well-documented phenomenon, but remarkably little is known about the regulation or function of anti-sense promoters and the non-coding RNAs they generate. Here we define at nucleotide resolution the divergent transcription start sites...
journal_title：Molecular cell
pub_type： 杂志文章
doi：10.1016/j.molcel.2015.04.006
更新日期：2015-06-18 00:00:00
