DRAM Triggers Lysosomal Membrane Permeabilization and Cell Death in CD4+ T Cells Infected with HIV
Open accessAbstract
Productive HIV infection of CD4(+) T cells leads to a caspase-independent cell death pathway associated with lysosomal membrane permeabilization (LMP) and cathepsin release, resulting in mitochondrial outer membrane permeabilization (MOMP). Herein, we demonstrate that HIV infection induces damage-regulated autophagy modulator (DRAM) expression in a p53-dependent manner. Knocking down the expression of DRAM and p53 genes with specific siRNAs inhibited autophagy and LMP. However, inhibition of Atg5 and Beclin genes that prevents autophagy had a minor effect on LMP and cell death. The knock down of DRAM gene inhibited cytochrome C release, MOMP and cell death. However, knocking down DRAM, we increased viral infection and production. Our study shows for the first time the involvement of DRAM in host-pathogen interactions, which may represent a mechanism of defense via the elimination of infected cells.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
DRAM1 provides a major contribution to lysosome-dependent cell death in HIV1-infected T cells by linking LMP to MOMP.
“The p53 effector DNA damage regulated autophagy modulator 1 (DRAM1) [773] provides a major contribution to lysosome-dependent cell death in HIV1-infected T cells by linking LMP to MOMP [770].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [770]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
IMPROVEMENTS IN EPOXY RESIN EMBEDDING METHODS
Luft, J. H. (1961) · The Journal of Cell Biology · doi:10.1083/jcb.9.2.409 · Cited by 10,243 · see citing works
Autophagy as a regulated pathway of cellular degradation.
Klionsky, D., & Emr, S. (2000) · Science · doi:10.1126/science.290.5497.1717 · Cited by 3,794 · see citing works
The role of autophagy during the early neonatal starvation period
Kuma, A., Hatano, M., Matsui, M., Yamamoto, A., Nakaya, H., Yoshimori, T., Ohsumi, Y., Tokuhisa, T., & Mizushima, N. (2004) · Nature · doi:10.1038/nature03029 · Cited by 2,865 · see citing works
Autophagy in Health and Disease: A Double-Edged Sword
Shintani, T., & Klionsky, D. J. (2004) · Science · doi:10.1126/science.1099993 · Cited by 2,531 · see citing works
Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
Klionsky, D. J., Abeliovich, H., Agostinis, P., Agrawal, D. K., Aliev, G., Askew, D. S., Baba, M., Baehrecke, E. H., Bahr, B. A., Ballabio, A., et al. (2008) · Autophagy · doi:10.4161/auto.5338 · Cited by 2,230 · see citing works
Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice.
Komatsu, M., Waguri, S., Koike, M., Sou, Y.-S., Ueno, T., Hara, T., Mizushima, N., Iwata, J.-I., Ezaki, J., Murata, S., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.035 · Cited by 2,124 · see citing works
Selective autophagy mediated by autophagic adapter proteins
Johansen, T., & Lamark, T. (2011) · Autophagy · doi:10.4161/auto.7.3.14487 · Cited by 1,730 · see citing works
Importance of the nef gene for maintenance of high virus loads and for development of AIDS
Kestier, H. W., Ringler, D. J., Mori, K., Panicali, D., Sehgal, P. K., Daniel, M. D., & Desrosiers, R. C. (1991) · Cell · doi:10.1016/0092-8674(91)90097-i · Cited by 1,593 · see citing works
Termination of autophagy and reformation of lysosomes regulated by mTOR
Yu, L., McPhee, C. K., Zheng, L., Mardones, G. A., Rong, Y., Peng, J., Mi, N., Zhao, Y., Liu, Z., Wan, F., et al. (2010) · Nature · doi:10.1038/nature09076 · Cited by 1,544 · see citing works
Identification of host proteins required for HIV infection through a functional genomic screen
Brass, A. L., Dykxhoorn, D. M., Benita, Y., Yan, N., Engelman, A., Xavier, R. J., Lieberman, J., & Elledge, S. J. (2008) · Science · doi:10.1126/science.1152725 · Cited by 1,449 · cited 1× · see citing works
“It has been suggested that autophagy is involved in HIV viral replication [23], in the death of uninfected CD4 T cells following the interaction of the HIV envelope glycoprotein and its co-receptor CXCR4 [24].”
BackgroundDRAM, a p53-Induced Modulator of Autophagy, Is Critical for Apoptosis
Crighton, D., Wilkinson, S., O'Prey, J., Syed, N., Smith, P., Harrison, P. R., Gasco, M., Garrone, O., Crook, T., & Ryan, K. M. (2006) · Cell · doi:10.1016/j.cell.2006.05.034 · Cited by 1,380 · see citing works
Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes
Shimizu, S., Kanaseki, T., Mizushima, N., Mizuta, T., Arakawa-Kobayashi, S., Thompson, C. B., & Tsujimoto, Y. (2004) · Nature Cell Biology · doi:10.1038/ncb1192 · Cited by 1,358 · see citing works
Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis
Sanjuan, M. A., Dillon, C. P., Tait, S. W. G., Moshiach, S., Dorsey, F., Connell, S., Komatsu, M., Tanaka, K., Cleveland, J. L., Withoff, S., et al. (2007) · Nature · doi:10.1038/nature06421 · Cited by 1,347 · see citing works
Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection
Mattapallil, J. J., Douek, D. C., Hill, B. J., Nishimura, Y., Martin, M. A., & Roederer, M. (2005) · Nature · doi:10.1038/nature03501 · Cited by 1,269 · see citing works
Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells
Li, Q., Duan, L., Estes, J. D., Ma, Z.-M., Rourke, T., Wang, Y., Reilly, C., Carlis, J. V., Miller, C. J., & Haase, A. T. (2005) · Nature · doi:10.1038/nature03513 · Cited by 950 · see citing works
Unveiling the roles of autophagy in innate and adaptive immunity
Levine, B., & Deretic, V. P. (2007) · Nature reviews. Immunology · doi:10.1038/nri2161 · Cited by 903 · see citing works
Takaoka, A., Hayakawa, S., Yanai, H., Stoiber, D., Negishi, H., Kikuchi, H., Sasaki, S., Imai, K., Shibue, T., Honda, K., et al. (2003) · Nature · doi:10.1038/nature01850 · Cited by 847 · see citing works
Eating Oneself and Uninvited Guests
Levine, B. (2005) · Cell · doi:10.1016/j.cell.2005.01.005 · Cited by 785 · see citing works
Guicciardi, M. E., Leist, M., & Gores, G. J. (2004) · Oncogene · doi:10.1038/sj.onc.1207512 · Cited by 716 · see citing works
LAMP proteins are required for fusion of lysosomes with phagosomes
Huynh, K. K., Eskelinen, E., Scott, C. C., Malevanets, A., Säftig, P., & Grinstein, S. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601511 · Cited by 694 · see citing works
Lysosomal Protease Pathways to Apoptosis
Stoka, V., Turk, B., Schendel, S. L., Kim, T., Cirman, T., Snipas, S. J., Ellerby, L., Bredesen, D. E., Freeze, H. H., Abrahamson, M., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008944200 · Cited by 673 · see citing works
Autophagy Protects against Sindbis Virus Infection of the Central Nervous System
Orvedahl, A., MacPherson, S., Sumpter, R., Tallóczy, Z., Zou, Z., & Levine, B. (2010) · Cell Host & Microbe · doi:10.1016/j.chom.2010.01.007 · Cited by 558 · see citing works
Autophagy pathway intersects with HIV-1 biosynthesis and regulates viral yields in macrophages
Kyei, G. B., Dinkins, C., Davis, A. S., Roberts, E., Singh, S. B., Dong, C., Wu, L., Kominami, E., Ueno, T., Yamamoto, A., et al. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200903070 · Cited by 509 · see citing works
Eating Oneself and Uninvited GuestsAutophagy-Related Pathways in Cellular Defense
Levine, B. (2005) · Cell · doi:10.1016/s0092-8674(05)00043-7 · Cited by 453 · see citing works
Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4
Espert, L. (2006) · Journal of Clinical Investigation · doi:10.1172/jci26185 · Cited by 447 · see citing works
Bidère, N., Lorenzo, H. K., Carmona, S., Laforge, M., Harper, F., Dumont, C., & Senik, A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301911200 · Cited by 435 · see citing works
Self-citationSpina, C. A., Kwoh, T. J., Chowers, M., Guatelli, J. C., & Richman, D. D. (1994) · The Journal of Experimental Medicine · doi:10.1084/jem.179.1.115 · Cited by 391 · see citing works
Blanchet, F. P., Moris, A., Nikolic, D. S., Lehmann, M., Cardinaud, S., Stalder, R., Garcia, E., Dinkins, C., Leuba, F., Wu, L. J., et al. (2010) · Immunity · doi:10.1016/j.immuni.2010.04.011 · Cited by 291 · see citing works
Multiple cell death pathways as regulators of tumour initiation and progression
Jäättelä, M. (2004) · Oncogene · doi:10.1038/sj.onc.1207513 · Cited by 283 · see citing works
Estaquier, J., Idziorek, T., Zou, W., Émilie, D., Farber, C., Bourez, J. M., & Ameisen, J. (1995) · The Journal of Experimental Medicine · doi:10.1084/jem.182.6.1759 · Cited by 273 · see citing works
Self-citationDoes autophagy have a license to kill mammalian cells?
Scarlatti, F., Granata, R., Meijer, A., & Codogno, P. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2008.101 · Cited by 271 · see citing works
Estaquier, J., Idziorek, T., BELS, F. D., et al. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.20.9431 · Cited by 252 · see citing works
Self-citationFehrenbacher, N., Bastholm, L., Kirkegaard‐Sørensen, T., Rafn, B., Bøttzauw, T., Nielsen, C. W., Weber, E., Shirasawa, S., Kallunki, T., & Jäättelä, M. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0463 · Cited by 242 · see citing works
Lysosomal destabilization in p53-induced apoptosis
Yuan, X., Li, W., Dalen, H., Lotem, J., Kama, R., Sachs, L., & Brunk, U. T. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.092135599 · Cited by 226 · see citing works
HIV-1 Directly Kills CD4+ T Cells by a Fas-independent Mechanism
Gandhi, R. T., Chen, B. K., Straus, S. E., et al. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.187.7.1113 · Cited by 201 · see citing works
Activation of the ATR-mediated DNA Damage Response by the HIV-1 Viral Protein R
Roshal, M., Kim, B., Zhu, Y., Nghiem, P., & Planelles, V. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303948200 · Cited by 200 · see citing works
HISTOCHEMICAL STUDIES OF LYSOSOMES AND LYSOSOMAL ENZYMES IN VIRUS-INFECTED CELL CULTURES
ALLISON, A. C., & Mallucci, L. (1965) · The Journal of Experimental Medicine · doi:10.1084/jem.121.3.463 · Cited by 175 · see citing works
Human immunodeficiency virus type-1 infection inhibits autophagy
Zhou, D.-J., & Spector, S. (2008) · AIDS (London) · doi:10.1097/qad.0b013e3282f4a836 · Cited by 164 · see citing works
Castedo, M., Ferri, K. F., Blanco, J., Roumier, T., Larochette, N., Barretina, J. G., Amendola, A., Nardacci, R., Métivier, D., Esté, J. A., et al. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.8.1097 · Cited by 145 · see citing works
Greenway, A. L., McPhee, D. A., Allen, K., Johnstone, R. W., Holloway, G., MILLS, J. S., Azad, A. A., Sankovich, S., & Lambert, P. F. (2002) · Journal of Virology · doi:10.1128/jvi.76.6.2692-2702.2002 · Cited by 140 · see citing works
HIV-1 Inhibits Autophagy in Bystander Macrophage/Monocytic Cells through Src-Akt and STAT3
Grol, J. V., Subauste, M. C., Andrade, R. M., Fujinaga, K., Nelson, J. A. E., & Subauste, C. S. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011733 · Cited by 130 · see citing works
HIV-1 Vpr-Induced Apoptosis Is Cell Cycle Dependent and Requires Bax but Not ANT
Andersen, J. L., DeHart, J. L., Zimmerman, E. S., Ardon, O., Kim, B., Jacquot, G., Bénichou, S., & Planelles, V. (2006) · PLoS Pathogens · doi:10.1371/journal.ppat.0020127 · Cited by 116 · see citing works
HIV induces lymphocyte apoptosis by a p53‐initiated, mitochondrial‐mediated mechanism
Genini, D., Sheeter, D. A., Rought, S. E., Zaunders, J. J., Susín, S. A., Kroemer, G., Richman, D. D., Carson, D. A., Corbeil, J., & Leoni, L. M. (2000) · The FASEB Journal · doi:10.1096/fj.00-0336fje · Cited by 114 · see citing works
Temporal Gene Regulation During HIV-1 Infection of Human CD4+ T CellsPreprint
Corbeil, J., Sheeter, D. A., Genini, D., Rought, S. E., Leoni, L. M., Du, P., Ferguson, M., Masys, D. R., Welsh, J. B., Fink, J. L., et al. (2001) · Genome Research · doi:10.1101/gr.180201 · Cited by 106 · see citing works
Lenardo, M. J., Angleman, S. B., Bounkeua, V., et al. (2002) · Journal of Virology · doi:10.1128/jvi.76.10.5082-5093.2002 · Cited by 91 · see citing works
Temporal Gene Regulation During HIV-1 Infection of Human CD4+ T CellsPreprint
Corbeil, J. (2001) · Genome Research · doi:10.1101/gr.gr-1802r · Cited by 82 · see citing works
Petit, F., Arnoult, D., Lelièvre, J., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m102671200 · Cited by 70 · see citing works
Cumont, M., Monceaux, V., Viollet, L., Lay, S., Parker, R., Hurtrel, B., & Estaquier, J. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402192 · Cited by 68 · see citing works
Self-citationBolton, D. L., Hahn, B.-I., Park, E. A., Lehnhoff, L. L., Hornung, F., & Lenardo, M. J. (2002) · Journal of Virology · doi:10.1128/jvi.76.10.5094-5107.2002 · Cited by 68 · see citing works
Guanidine alkaloid analogs as inhibitors of HIV-1 Nef interactions with p53, actin, and p56 lck
Olszewski, A., Sato, K., Aron, Z. D., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0406040101 · Cited by 67 · see citing works
Imbeault, M., Lodge, R., Ouellet, M., & Tremblay, M. J. (2009) · Virology · doi:10.1016/j.virol.2009.07.009 · Cited by 66 · see citing works
Sanfridson, A., Hester, S., & Doyle, C. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.3.873 · Cited by 62 · see citing works
Monceaux, V., Estaquier, J., Février, M., et al. (2003) · AIDS · doi:10.1097/00002030-200307250-00002 · Cited by 62 · see citing works
Self-citationHurtrel, B., Petit, F., Arnoult, D., Müller-Trutwin, M. C., Silvestri, G., & Estaquier, J. (2005) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401600 · Cited by 59 · see citing works
Self-citationLi, N., Zheng, Y., Chen, W., Wang, C., Liu, X., He, W., Xu, H., & Cao, X. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-2333 · Cited by 58 · see citing works
Tat-Induced FOXO3a Is a Key Mediator of Apoptosis in HIV-1-Infected Human CD4+ T Lymphocytes
Dabrowska, A., Kim, N., & Aldovini, A. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.12.8460 · Cited by 58 · see citing works
Imbeault, M., Ouellet, M., & Tremblay, M. J. (2009) · Retrovirology · doi:10.1186/1742-4690-6-5 · Cited by 56 · see citing works
Shvets, E., & Elazar, Z. (2008) · Autophagy · doi:10.4161/auto.6823 · Cited by 51 · see citing works
Laforge, M., Petit, F., Estaquier, J., & Senik, A. (2007) · Journal of Virology · doi:10.1128/jvi.00597-07 · Cited by 49 · see citing works
Self-citationViollet, L., Monceaux, V., Petit, F., Fang, R. H. T., Cumont, M., Hurtrel, B., & Estaquier, J. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.10.6685 · Cited by 42 · see citing works
Self-citationMoutouh, L., Estaquier, J., Richman, D. D., et al. (1998) · Journal of Virology · doi:10.1128/jvi.72.10.8061-8072.1998 · Cited by 37 · see citing works
Self-citationActivation of Isolated Lysosomes by Poliovirus-infected Cell Extracts
Thacore, H. R., & WOLFF, D. A. (1968) · Nature · doi:10.1038/2181063a0 · Cited by 33 · see citing works
Modulation of the ARF-p53 Pathway by the Small DNA Tumor Viruses
O’Shea, C. C., & Fried, M. (2005) · Cell Cycle · doi:10.4161/cc.4.3.1555 · Cited by 29 · see citing works
Duus, K., Miller, E. D., Smith, J. A., Kovalev, G. I., & Su, L. (2001) · Journal of Virology · doi:10.1128/jvi.75.8.3916-3924.2001 · Cited by 24 · see citing works
Disease progression in macaques with low SIV replication levels: on the relevance of TREC counts
Fang, R. H. T., Khatissian, E., Monceaux, V., et al. (2005) · AIDS · doi:10.1097/01.aids.0000166089.93574.5a · Cited by 23 · see citing works
Lysosomal Changes in Lytic and Nonlytic Infections With the Simian Vacuolating Virus (SV40) 2
Allison, A. C., & Black, P. H. (1967) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/39.4.775 · Cited by 19 · see citing works
Lelièvre, J., Petit, F., Perrin, L. H., et al. (2004) · AIDS Research and Human Retroviruses · doi:10.1089/aid.2004.20.1230 · Cited by 15 · see citing works
Host-Cell Lysosomal Response to Two Strains of Herpes Simplex Virus
Fine, D. L., Lake, R. S., & LUDWIG, E. H. (1970) · Journal of Virology · doi:10.1128/jvi.5.2.226-229.1970 · Cited by 7 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Self-consumption: the interplay of autophagy and apoptosis
Mariño, G., Niso-Santano, M., Baehrecke, E. H., & Kroemer, G. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3735 · Cited by 2,172 · see citing works
Lysosomal cell death mechanisms in aging
Gómez-Sintes, R., Ledesma, M. D., & Boya, P. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.02.009 · Cited by 216 · see citing works
Serrano‐Puebla, A., & Boya, P. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12966 · Cited by 204 · see citing works
- Authors
- Laforge, M., Limou, S., Harper, F., Casartelli, N., Rodrigues, V., Silvestre, R., Haloui, H., Zagury, J.-F., Senik, A., & Estaquier, J.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Conservatoire National des Arts et Métiers (FR)
- Institut Pasteur (FR)
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-05-02
- Volume
- 9
- Issue
- 5
- Pages
- e1003328
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC3642063
- OpenAlex
- W2000413234
- Cited by
- 70
- References
- 68
- Citations by year
- 2025: 5 · 2024: 9 · 2023: 4 · 2022: 6 · 2021: 5 · 2020: 5 · 2019: 7 · 2018: 8 · 2017: 4 · 2016: 4 · 2015: 6 · 2014: 5 · 2013: 2
- FWCI
- 4.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Centre National de la Recherche Scientifique
- Ministério da Ciência, Tecnologia e Ensino Superior
- Fundação para a Ciência e a Tecnologia (/2009)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Keywords
- DRAM, lysosomal membrane permeabilization, CD4+ T cells, HIV infection, p53, autophagy, caspase-independent cell death, mitochondrial outer membrane permeabilization, cytochrome c release, host-pathogen interaction, viral clearance, ATG5, Beclin-1
- MeSH terms
- Autophagy-Related Protein 5, Autophagy, Female, Gene Expression Regulation, HIV, Humans, Intracellular Membranes, Lysosomes, Male, Membrane Proteins, Microtubule-Associated Proteins, Permeability, CD4-Positive T-Lymphocytes, HIV Infections, Tumor Suppressor Protein p53, Cytochromes c, Host-Pathogen Interactions
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
