Inhibition of transcriptional activation and cell proliferation activities of adenovirus E1A by the unique N-terminal domain of CtBP2.
The 243-residue E1A protein of adenovirus induces cellular proliferation, at least partly by regulating the transcription of cellular genes. This E1A function requires E1A N-terminal region and conserved regions 1 and 2 (CR1 and CR2), which interact with histone acetyl transferases, p400 chromatin-modifying complex and the Rb family proteins. A PLDLS motif at the E1A C-terminal (CR4) region, interacts with the C-terminal binding proteins (CtBP1 and CtBP2), and antagonizes some E1A functions. In this report, we discovered that the transcriptional activation function of E1A was specifically repressed by a short N-terminal domain unique to CtBP2. The CtBP2-mediated repression of E1A transcriptional activation activity is independent of histone deacetylases, which can be recruited by CtBP1/2 proteins to inhibit transcription. Fusion of the CtBP2 N-terminal 20 residues to the E1A C-terminal region rendered E1A to be inactive in transcriptional activation without interfering with E1A's ability to interact with major cofactors such as pRb, p400 and p300. Substitution of the N-terminal domain of CtBP1 for the CtBP2 domain in E1A-CtBP2 fusion partially restored the transactivation activity of E1A. In a cell-proliferation model utilizing primary baby rat kidney cells and retrovirally expressed E1A, the ability of E1A to induce cellular proliferation was strongly inhibited when the CtBP2 N-terminal region was fused to E1A. These results are consistent with a hypothesis that CtBP2 may inhibit E1A induced cell proliferation by antagonizing the transcriptional activation function controlled by the N-terminal region of E1A.
Zhao
L-J
LJ
Institute for Molecular Virology, Saint Louis University Health Sciences Center, Doisy Research Center, St Louis, MO 63104, USA.
Subramanian
T
T
Chinnadurai
G
G
D017500:Adenovirus E1A Proteins / Q000502:physiology*; D000429:Alcohol Oxidoreductases / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000502:physiology*; D051381:Rats; D015533:Transcriptional Activation / Q000502:physiology*
D017500:Adenovirus E1A Proteins; D056970:Co-Repressor Proteins; D009419:Nerve Tissue Proteins; D000429:Alcohol Oxidoreductases; C421248:CTBP2 protein, human