HTLV-1 and HIV-1 are retroviruses involved in different human diseases. However, following infection, these viruses inter into a latent state. Tax and Tat are regarded as trans-activators of HTLV-1 and HIV-1 respectively. As it known, during the latent state the infected cells contain low Tax and Tat protein levels, so the activation of these viruses must be independent of these proteins. Here we focus on exploring the mechanism of activation of these viruses by 12-O-tetradecanoylphorbol-13-acetate (TPA), which is a potent activator of protein kinase C (PKC) and considered as a stress-inducing agent. Our results showed that short exposure to TPA considerably stimulated only the HIV-1 LTR expression, while long exposure stimulated only the HTLV-1 LTR and that their activation is agonized or antagonized by PKC respectively. It was found that TPA induced interaction between the transcriptional factors Spl and P53 producing Sp1-p53 complex which strongly interacted with c-Jun only after short exposure to TPA. In addition, TPA treatment highly induced the expression of CREB which attached to the Sp1 -p53 complex mainly after a long exposure to TPA. A strong binding of spl, p53 and CREB proteins with HTLV-1 LTR and strong binding of NF-kappa B with HIV-1 LTR were observed after long (24 h) and short (6 h) exposures to TPA respectively by Chip assay. These results support the possibility that sp1-p53 and CREB are involved in the TPA induced HTLV-1 LTR expression while TPA activation of HIV-1 LTR seems to be dependent on PKC activity through the NF-kappa B pathway. (C) 2018 Elsevier Inc. All rights reserved.