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Sv40 large t antigen

The meaning of «sv40 large t antigen»

SV40 large T antigen (Simian Vacuolating Virus 40 TAg) is a hexamer protein that is a dominant-acting oncoprotein derived from the polyomavirus SV40. TAg is capable of inducing malignant transformation of a variety of cell types. The transforming activity of TAg is due in large part to its perturbation of the retinoblastoma (pRb)[1] and p53 tumor suppressor proteins.[2] In addition, TAg binds to several other cellular factors, including the transcriptional co-activators p300 and CBP, which may contribute to its transformation function.[3]

TAg is a product of an early gene transcribed during viral infection by SV40, and is involved in viral genome replication and regulation of host cell cycle. SV40 is a double-stranded, circular DNA virus belonging to the Polyomaviridae (earlier Papovavirus) family, Orthopolyomavirus genus. Polyomaviruses infect a wide variety of vertebrates and cause solid tumours at multiple sites. SV40 was isolated by Sweet and Maurice Hilleman in 1960 in primary monkey kidney cell cultures being used to grow Sabin OPV.[4]

The TAg has a CUL7-binding domain, a TP53-binding domain, a Zinc finger, and a Superfamily 3 ATPase/Helicase domain. It has two motifs, one for nuclear localization signal, the other being the LXCXE motif.[5]

After entering the cell, the viral genes are transcribed by host cell RNA polymerase II to produce early mRNAs. Because of the relative simplicity of the genome, polyomaviruses are heavily dependent on the cell for transcription and genome replication. The cis-acting regulatory element surrounding the origin of replication directs transcription, and T-antigen directs transcription and replication.

SV40 DNA replication is initiated by binding of large T-antigen to the origin region of the genome. The function of T-antigen is controlled by phosphorylation, which attenuates the binding to the SV40 origin. Protein-protein interactions between T-antigen and DNA polymerase-alpha directly stimulate replication of the virus genome.

T-antigen also binds and inactivates tumor suppressor proteins (p53, p105-Rb). This causes the cells to leave G1 phase and enter into S phase, which promotes DNA replication.

The SV40 genome is very small and does not encode all the information necessary for DNA replication. Therefore, it is essential for the host cell to enter S phase, when cell DNA and the viral genome are replicated together. Therefore, in addition to increasing transcription, another function of T-antigen is to alter the cellular environment to permit virus genome replication.

The SV40 large T-antigen has been used as a model protein to study nuclear localization signals (NLSs).[6] It is imported into the nucleus by its interaction with importin α.[7] The NLS sequence is PKKKRKV.[6]

SV40 large TAg, other polyomavirus large T antigens, adenovirus E1a proteins, and oncogenic human papillomavirus E7 proteins share a structural motif that encodes a high-affinity pRb-binding domain.[8][9] This motif is characterized by an Asp, Asn or Thr residue followed by three invariant amino acids, interspersed with non-conserved amino acids (designated by x, where x cannot be a Lys or Arg residue).[9] A negatively charged region frequently follows carboxy-terminal to the pRb-binding domain.[9]

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