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The latency-associated nuclear antigen (LANA-1) or latent nuclear antigen (LNA, LNA-1) is a Kaposi's sarcoma-associated herpesvirus (KSHV) latent protein initially found by Moore and colleagues as a speckled nuclear antigen present in primary effusion lymphoma cells that reacts with antibodies from patients with KS.[1] It is the most immunodominant KSHV protein identified by Western-blotting as 222–234 kDa double bands migrate slower than the predicted molecular weight.[2] LANA has been suspected of playing a crucial role in modulating viral and cellular gene expression.[3][4][5] It is commonly used as an antigen in blood tests to detect antibodies in persons that have been exposed to KSHV.[6][7]

KSHV or Human herpesvirus 8 (HHV-8) has been identified as the etiological agent of Kaposi’s sarcoma (KS) and certain AIDS-associated lymphomas. As KSHV establishes latent infection in tumorous foci, it invariably expresses high levels of the viral LANA protein, which is necessary and sufficient to maintain the KSHV episome.

Encoded by ORF73, LANA-1 is one of few HHV-8 encoded proteins that is highly expressed in all latently infected tumour cells; specifically, it is a phosphoprotein with an acidic internal repeat domain flanked by a carboxy-terminal domain and an amino-terminal domain.[5] LANA-1 acts as a transcriptional regulator, and it has been implicated directly in oncogenesis because of its ability to bind to the tumour-suppressing protein p53 and to the retinoblastoma protein pRb. This leads to the inactivation of p53-dependent promoters and induction of E2F-dependent genes.[8][9]

Studies have also shown that LANA-1 can transactivate the promoter of the reverse transcriptase subunit of the human telomerase holoenzyme,[9] thus overextending a critical step in cellular transformation.[10] Paradoxically, LANA-1 has been shown to be involved in transcriptional repression [11][12][13] and can, moreover, interact with the mSin3/HDAC1 co-repressor complex.[12]

It has been also shown to interact with and inhibit the ATF4/CREB2 transcription factor that interacts with the basic transcription machinery[14] and to bind with two human chromosome-associated cellular proteins, MeCP2 and DEK.[12]

LANA-1 is associated with cellular chromatin and stays on the chromosomes during cell division.[15] It maintains the viral genomes during cell division by tethering the viral episomes to the chromosomes.[16] It binds directly to replication origin recognition complexes (ORCs) that are primarily associated with the terminal repeat (TR) region of the HHV-8 genome.[17]

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  • Are We Living In the Sixth Extinction?
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Transcription

[MUSIC] The California Golden Bear The Great Auk The Passenger pigeon The Tasmanian tiger The Pinta Island tortoise The Golden toad All dead. And the killer is right there in the room with you. [MUSIC] The walls of France’s Lascaux cave hold some of humankind’s earliest art, almost mythical species: a wooly rhinoceros, enormous-antlered Megaloceros elk and massive aurochs. The artists lived on, but those cave walls are the last place that those animals still run. They’re gone. Extinct. We all pretty much understand extinction, it’s when a species kicks the proverbial bucket, it rides off into the great biological sunset, bites the dust from whence it came and shall return, which is all just a pretty way of saying that every last one of them dies. Even kids are used to the idea that sometimes groups of living things just… don’t exist anymore. Okay, mostly don’t exist. But extinction, as a thing, is a surprisingly new concept. In the 1790’s, by studying various fossils, naturalist George Cuvier was the first to show that they were not from living, yet undiscovered creatures, as many thought, but from what he called “lost species”. In the decades to come, scientists like Charles Lyell and ol' Chuck Darwin began to popularize the idea that Earth’s processes, like geology, evolution, and even extinction, did occur, just very, very, verrrry slowly. So slowly that we’d surely never actually see something go extinct. The idea of so-called catastrophic change was just impossible… It wasn’t until the 1980’s that scientists were able to shake that idea. Geologist Walter Alvarez was puzzled by the sudden disappearance of tiny aquatic fossils between two rock layers that dated from about 66 million years ago, the same age as the last dinosaurs. With the help of his Nobel Prize winning father, he analyzed the chemistry of that boundary and found iridium levels that were off the charts. Now, there’s usually not much iridium in Earth’s crust, but it’s very common in asteroids. So Alvarez’s theory? A 10-km wide rock collided with Earth, wiping out 75% of Earth’s plants and animals. To be honest scientists kinda laughed at it… until the 1991 discovery of the Chicxulub crater near the Yucatan peninsula finally settled it. Everything alive today is a descendent of a survivor of that terrible, horrible, no good, very bad day, the so-called Cretaceous-Paleogene mass extinction event, the most recent of the Big 5. You should feel pretty lucky. When we look at all of Earth’s fossil record together, 98% of the species that have ever lived are extinct,. Only they haven’t always disappeared at a constant rate. In the history of life on Earth, we know of 5 different mass extinctions, when a majority of life on Earth at the time disappeared in the blink of a geologic eye. Besides the most recent dino-killer, there’s the Triassic-Jurassic, Late Devonian, Ordivician-Silurian, and the worst of all, the End Permian. This mother of mass extinctions wiped out as many as 96% of Earth’s species, so it got the best nickname: The Great Dying. We’ve learned about all these just in time to get some bad news: We are in the 6th mass extinction, and this time, we are the asteroid. The hard facts of life mean that even when things are going pretty well on Earth, there’s a background rate of extinction. Among mammals, for instance, we’d expect to see one species to go extinct every 700 years, or maybe one amphibian every thousand years. Studies of current extinction rates say we’re roughly one thousand times past that, and in some groups, like amphibians, are disappearing forty-five thousand times faster than normal. And since there are so many species still unknown or uncharacterized, all of those numbers are probably underestimates. Goodbye, gastric brooding frog, Pyrenean ibex, the Fomosan clouded leopard. We could have been friends. So how do we know we’re to blame? Around 13,000 years ago, as Earth thawed from its most recent big freeze, all of our favorite weird megafauna like the wooly mammoth, Smilodon, and our old friend Megatherium disappeared from the Earth, thanks to a changing climate and the invention of sharp stabby hunting tools. I really wish we had saved the 8-foot long beaver though. That would be awesome. Along the way, through hunting and farming, humans have been altering ecosystems in small but significant ways, but since the Industrial Revolution, man we have really kicked it into overdrive. With the exception of maybe the first bacteria to breathe oxygen into the air, no living thing has ever altered life on Earth to the degree that we have, which is why scientists now refer to current epoch as the Anthropocene. "We are the ultimate problem. There are 7 billion people on the planet, we tend to destroy critical habitats where species live, we tend to be warming the planet, we tend to be very careless about moving species around the planet." According to a 2014 paper by Stuart Pimm in Science (link in the doobly do), the main cause of the current extinction is human population growth and increased consumption. But those two things lead to a whole mess of threats: The most obvious are climate change and habitat destruction. Scientists found that most land species have very small ranges, so they can’t just pack up and move when we cut down their forest or turn it into a desert. Ocean species have more freedom to move to better waters, unless they’re coral reefs, but thanks to the highest atmospheric CO2 concentrations in 800,000+ years turning the oceans more acidic, anything with a calcium based shell has nowhere to run… or swim. If current trends hold up and the ocean hits pH 7.8 by end of century, it could wipe out ⅓ of the species in the ocean. Then there’s the invaders! Thanks to a species of snake hitching a ride on military cargo in the 1940s, Guam has lost all of its native birds. "I have had it with these (invasive) snakes on this (Guam-bound cargo) plane" In Africa’s Lake Victoria, 100s of species of cichlid fish species vanished after fishermen introduced the Nile Perch. Go us! We’re erasing species faster than we can even name them. Stanford’s Rodolfo Dirzo says that in the past 40 years, invertebrate populations, which might make up 97% of species on Earth, have declined 45% worldwide, and that’s just the ones we know about. (Link in the doobly do to that one too) You have to feel worst for the amphibians. Over the past 350 million years, they’ve survived multiple mass extinctions, but this time we’re giving them all we’ve got. Dirzo gives this loss of animal life a rather harmless sounding name: Defaunation. But there is nothing cute about it. There is not a group of living things on Earth today that is not threatened by the current and coming extinction. That includes us. Extinction is about more than gorillas, tigers, polar bears, and rhinos, and the dozens of other “famous” or “charismatic” species out there. Those are all important and worth saving, but we need to care just as much about the humble beetles, the ugly little worms, and the slimy frogs. Every species, big or small, panda or protozoa, is important and worth saving, whether or not we understand exactly why it’s worth saving. John Muir once said, “When we try to pick out anything by itself we find that it is bound fast by a thousand invisible cords that cannot be broken, to everything in the universe.” I’ve put some links down in the description where you can get to know some of Earth’s less-loved endangered species. Go make friends with one. Our knowledge and understanding of the planet’s ecosystems may be incomplete, but our effect on them knows no bounds. I hope the same tools and technology that we’ve used to push life on Earth to the edge might also give us power to bring ‘em back. So what are we gonna do? Let’s talk about it down there. Stay curious. If you want to read more about the brilliant and tragic stories of extinction in this age of humans, check out "The Sixth Extinction" by Elizabeth Kolbert, link in the description.

Notes and references

  1. ^ Moore PS, Gao SJ, Dominguez G, Cesarman E, Lungu O, Knowles DM, Garber R, Pellett PE, McGeoch DJ, Chang Y (January 1996). "Primary characterization of a herpesvirus agent associated with Kaposi's sarcoma". Journal of Virology. 70 (1): 549–58. doi:10.1128/JVI.70.1.549-558.1996. PMC 189843. PMID 8523568.
  2. ^ Gao SJ, Kingsley L, Hoover DR, Spira TJ, Rinaldo CR, Saah A, Phair J, Detels R, Parry P, Chang Y, Moore PS (July 1996). "Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma". The New England Journal of Medicine. 335 (4): 233–241. doi:10.1056/NEJM199607253350403. PMID 8657239.
  3. ^ Kedes DH, Lagunoff M, Renne R, Ganem D (November 1997). "Identification of the gene encoding the major latency-associated nuclear antigen of the Kaposi's sarcoma-associated herpesvirus". The Journal of Clinical Investigation. 100 (10): 2606–10. doi:10.1172/JCI119804. PMC 508462. PMID 9366576.
  4. ^ Kellam P, Boshoff C, Whitby D, Matthews S, Weiss RA, Talbot SJ (1997). "Identification of a major latent nuclear antigen, LNA-1, in the human herpesvirus 8 genome". Journal of Human Virology. 1 (1): 19–29. PMID 10195227.
  5. ^ a b Rainbow L, Platt GM, Simpson GR, et al. (August 1997). "The 222- to 234-kilodalton latent nuclear protein (LNA) of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) is encoded by orf73 and is a component of the latency-associated nuclear antigen". Journal of Virology. 71 (8): 5915–21. doi:10.1128/JVI.71.8.5915-5921.1997. PMC 191847. PMID 9223481.
  6. ^ Gao SJ, Kingsley L, Li M, Zheng W, Parravicini C, Ziegler J, Newton R, Rinaldo CR, Saah A, Phair J, Detels R, Chang Y, Moore PS (August 1996). "KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma". Nature Medicine. 2 (8): 925–928. doi:10.1038/nm0896-925. PMID 8705864. S2CID 10275045.
  7. ^ Kedes DH, Operskalski E, Busch M, Kohn R, Flood J, Ganem D (August 1996). "The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission". Nature Medicine. 2 (8): 918–924. doi:10.1038/nm0896-918. PMID 8705863. S2CID 36556102.
  8. ^ Friborg J, Kong W, Hottiger MO, Nabel GJ (1999). "p53 inhibition by the LANA protein of KSHV protects against cell death". Nature. 402 (6764): 889–94. doi:10.1038/47266. PMID 10622254. S2CID 4345286.
  9. ^ a b Komatsu T, Ballestas ME, Barbera AJ, Kaye KM (March 2002). "The KSHV latency-associated nuclear antigen: a multifunctional protein". Frontiers in Bioscience. 7 (1–3): d726–30. doi:10.2741/komatsu. PMID 11861213.
  10. ^ Jeong JH, Orvis J, Kim JW, McMurtrey CP, Renne R, Dittmer DP (April 2004). "Regulation and autoregulation of the promoter for the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus". The Journal of Biological Chemistry. 279 (16): 16822–31. doi:10.1074/jbc.M312801200. PMID 14742422.
  11. ^ Garber AC, Hu J, Renne R (July 2002). "Latency-associated nuclear antigen (LANA) cooperatively binds to two sites within the terminal repeat, and both sites contribute to the ability of LANA to suppress transcription and to facilitate DNA replication". The Journal of Biological Chemistry. 277 (30): 27401–11. doi:10.1074/jbc.M203489200. PMID 12015325.
  12. ^ a b c Krithivas A, Young DB, Liao G, Greene D, Hayward SD (October 2000). "Human herpesvirus 8 LANA interacts with proteins of the mSin3 corepressor complex and negatively regulates Epstein-Barr virus gene expression in dually infected PEL cells". Journal of Virology. 74 (20): 9637–45. doi:10.1128/JVI.74.20.9637-9645.2000. PMC 112396. PMID 11000236.
  13. ^ Schwam DR, Luciano RL, Mahajan SS, Wong L, Wilson AC (September 2000). "Carboxy terminus of human herpesvirus 8 latency-associated nuclear antigen mediates dimerization, transcriptional repression, and targeting to nuclear bodies". Journal of Virology. 74 (18): 8532–40. doi:10.1128/JVI.74.18.8532-8540.2000. PMC 116365. PMID 10954554.
  14. ^ Lim C, Sohn H, Gwack Y, Choe J (November 2000). "Latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) binds ATF4/CREB2 and inhibits its transcriptional activation activity". The Journal of General Virology. 81 (Pt 11): 2645–52. doi:10.1099/0022-1317-81-11-2645. PMID 11038375.
  15. ^ Szekely L, Chen F, Teramoto N, et al. (June 1998). "Restricted expression of Epstein-Barr virus (EBV)-encoded, growth transformation-associated antigens in an EBV- and human herpesvirus type 8-carrying body cavity lymphoma line". The Journal of General Virology. 79 (Pt 6): 1445–52. doi:10.1099/0022-1317-79-6-1445. PMID 9634087.
  16. ^ Ballestas ME, Chatis PA, Kaye KM (April 1999). "Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen". Science. 284 (5414): 641–4. doi:10.1126/science.284.5414.641. PMID 10213686.
  17. ^ Verma SC, Lan K, Choudhuri T, Robertson ES (April 2006). "Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen modulates K1 expression through its cis-acting elements within the terminal repeats". Journal of Virology. 80 (7): 3445–58. doi:10.1128/JVI.80.7.3445-3458.2006. PMC 1440413. PMID 16537612.
This page was last edited on 14 August 2023, at 11:45
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