large T

Large T is a nuclear protein that can be divided into two domains. It has two independent nuclear localization signals. Large T is a DNA binding protein that oligomerizes using a zinc finger. Acting as a helicase, large T binds ATP. In the N-terminus large T binds tumor suppressors of the Rb family. It also binds hsc 70 through its J domain. Phosphorylation of large T at the end of the C-terminal domain can regulate its activity in DNA replication.

Large T is a protein with multiple functions. These are related on the one hand to its role as an initiator of viral DNA replication and on the other to its ability to promote cell cycle progression. The protein is capable of blocking differentiation of cells, of making embryo cells immortal, and of inducing programmed cell death. The C-terminal domain is sufficient for initiation of viral DNA replication is the cellular environment is right, that is the cell cycle is progressing. Phosphorylation of threonine 278 by cyclin/cdks acts as a biosensor. The N-terminal domain is involved in regulating cell cycle progression.

Much of LT function associated with cell cycle depend on its interaction with members of the Rb tumor suppressor family. The ability of the N-terminal domain to promote cell cycle progression, to immortalize, to induce apoptosis and to block differentiation depends on the association of large T with Rb family members. Rb family members regulate transcription factors of the E2F family, which are important for cell cycle progression. Large T disrupts E2F/Rb interactions. It turns out that much of the ability of LT to affect Rb family members depends on a large T J domain. This J domain allows interaction with hsc70, a member of the DnaK family. This connects LT to molecular chaperones of the DnaJ/DnaK family.

There remain additional unidentified functions in LT that induce cell cycle progression.