LANA

The latency-associated nuclear antigen or LANA-1, is a Kaposi's sarcoma-associated herpesvirus (KSHV) latent protein which has been suspected of playing a crucial role in modulating viral and cellular gene expression. [cite journal|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=9366576|author=Kedes D.H., Lagunoff M., Renne R., Ganem D.|title=Identification of the gene encoding the major latency-associated nuclear antigen of the Kaposi's sarcoma-associated herpesvirus.| journal=Journal of Clinical Investigation. |year=1997|month=|day=|volume=100|pages=2610-2606|id=|doi=] [cite journal|url=http://www.molecular-cancer.com/pubmed/10195227 |author=Kellam P., Boshoff C., Whitby D., Matthews S., Weiss R.A., Talbot S.J|title= Identification of a major latent nuclear antigen, LNA-1, in the human herpesvirus 8 genome.| journal=Journal of Human Virology.|year=1997|month=|day=|volume=1|pages=19-29|id=|doi=] cite journal|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=9223481|author=Rainbow L., Platt G.M., Simpson G.R., Sarid R., Gao S.J., Stoiber H., Herrington C.S., Moore P.S., Schulz T.F.|title=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=Journal of Virology.|year=1997|month=|day=|volume=71|pages=5915-5921|id=|doi=]

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 222–234 kDa phosphoprotein with an acidic internal repeat domain flanked by a carboxy-terminal domain and an amino-terminal domain. 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. [cite journal|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=10622254|author= Friborg J. Jr., Kong W., Hottiger M.O., Nabel G.J.|title= p53 inhibition by the LANA protein of KSHV protects against cell death.| journal=Nature.|year=1999|month=|day=|volume=402|pages=889-894|id=|doi=] [cite journal|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=11861213|author= Komatsu T., Ballestas M.E., Barbera A.J., Kaye K.M.|title=The KSHV latency-associated nuclear antigen: a multifunctional protein.| journal= Front Bioscience.|year=2002|month=|day=|volume=7|pages=726-730|id=|doi=]

Studies have also shown that LANA-1 can transactivate the promoter of the reverse transcriptase subunit of the human telomerase holoenzyme [cite journal|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=11861213|author= Knight J.S., Cotter M.A. 2nd, Robertson E.S.|title= The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus transactivates the telomerase reverse transcriptase promoter.| journal= Journal of Biological Chemistry.|year=2001|month=|day=|volume=276|pages=22971-22978|id=|doi=] , thus overextending a critical step in cellular transformation. [cite journal|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=14742422|author=Jeong J.H., Orvis J., Kim J.W., McMurtrey C.P., Renne R., Dittmer D.P.|title= Regulation and autoregulation of the promoter for the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus.| journal= Journal of Biological Chemistry.|year=2004|month=|day=|volume=279|pages=16822-16831|id=|doi=] Paradoxically, LANA-1 has been shown to be involved in transcriptional repression [cite journal|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=12015325|author=Garber AC, Hu J, Renne R.|title=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.|journal=Journal of Biological Chemistry.|year=2002|month=|day=|volume=277|pages=27401-27411|id=|doi=] cite journal|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=11000236|author=Krithivas A, Young DB, Liao G, Greene D, Hayward SD.|title=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=Journal of Virology.|year=2000|month=|day=|volume=74|pages=9637-9645|id=|doi=] [cite journal|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=10954554|author=Schwam DR, Luciano RL, Mahajan SS, Wong L, Wilson AC.|title=Carboxy terminus of human herpesvirus 8 latency-associated nuclear antigen mediates dimerization, transcriptional repression, and targeting to nuclear bodies. |journal= Journal of Virology.|year=2000|month=|day=|volume=74|pages=8532-8540|id=|doi=] and can, moreover, interact with the mSin3/HDAC1 co-repressor complex.

It has been also shown to interact with and inhibit the ATF4/CREB2 transcription factor that interacts with the basic transcription machinery [cite journal|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=11038375|author=Lim C, Sohn H, Gwack Y, Choe J.|title=Latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) binds ATF4/CREB2 and inhibits its transcriptional activation activity.|journal= Journal of General Virology. |year=2000|month=|day=|volume=81|pages=2645-2652|id=|doi=] and to bind with two human chromosome-associated cellular proteins, MeCP2 and DEK.

LANA-1 is associated with cellular chromatin and stays on the chromosomes during cell division. [cite journal|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=9634087|author=Szekely L, Chen F, Teramoto N, Ehlin-Henriksson B, Pokrovskaja K, Szeles A, Manneborg-Sandlund A, Lowbeer M, Lennette ET, Klein G|title=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. |journal= Journal of General Virology. |year=1998|month=|day=|volume=76|pages=1445-1452|id=|doi=] It maintains the viral genomes during cell division by tethering the viral episomes to the chromosomes. [cite journal|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=10213686|author=Ballestas ME, Chatis PA, Kaye KM|title=Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen.| journal=Science. |year=1999|month=|day=|volume=284|pages=641-644|id=|doi=] It binds directly to replication origin recognition complexes (ORCs) that are primarily associated with the terminal repeat (TR) region of the HHV-8 genome. [cite journal|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=16537612|author=Verma SC, Lan K, Choudhuri T, Robertson ES|title=Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen modulates K1 expression through its cis-acting elements within the terminal repeats. |journal=Journal of Virology|year=2006|month=|day=|volume=80|pages=3445-3458|id=|doi=]

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