SV40 вирусының үлкен T антигені және оның қатерлі трансформацияға әсері

Proto oncogene derived from polyomavirus SV40

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) and p53 tumor suppressor proteins. In addition, TAg binds to several other cellular factors, including the transcriptional co activators p300 and CBP, which may contribute to its transformation function. Similar proteins from related viruses are known as large tumor antigen in general. 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.

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.

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). It is imported into the nucleus by its interaction with importin α. The NLS sequence is PKKKRKV. A diagnostic pattern for a high affinity pRb binding domain was refined using an artificial intelligence pattern induction program running on a massively parallel supercomputer (Connection Machine 2). The 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). For example, mutation of the invariant Glu at position 107 to Lys 107 completely abolishes transforming activity. have demonstrated the biophysical basis for the interaction between this region of TAg and pRb. TAg residues 103 to 109 form an extended loop structure that binds tightly in a surface groove of pRb. This is likely due to the fact that the binding surface on pRb features six lysine residues, which will tend to repel positive residues within or flanking the Leu – x – Cys – x – Glu sequence.