p73, a member of the p53 family, is expressed from two separate promoters, generating TA and ΔN variants. Each variant potentially encodes at least seven alternatively spliced isoforms (α-η). Interestingly, we and others have shown that the α isoform of p73 has a weaker transcriptional activity than the α isoform. Because the α isoform has an extended C terminus consisting of a sterile α motif (SAM) and an extreme C terminus, it appears that the C terminus is inhibitory. However, how the C terminus inhibits the transcriptional activity of p73 has not been determined. Here, we found that both the SAM and the extreme C terminus exert their inhibitory activity by preventing the accessibility of p300/CBP to the activation domain in p73. Specifically, we showed that the SAM and the extreme C terminus together or individually are capable of repressing the function of p73 activation domain, but neither interacts directly with the activation domain, or suppresses the DNA-binding activity, of the p73 protein. We also showed that the intact state of the SAM and the extreme C terminus is essential for their inhibitory functions such that a small deletion of either the SAM or the extreme C terminus abolishes its inhibitory activity. Furthermore, we showed that both inhibitory domains in the C terminus are capable of suppressing the function of a cis heterologous activation domain from p53 or Gal4. Finally, we showed that both inhibitory domains suppress the ability of p73 to interact with the transcriptional coactivators p300/CBP that are necessary for the initiation of transcription. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.