Particularly, the incomplete inhibitory effect of CRTC1M1 suggested that compromising CRTC1 alone is insufficient to abrogate the activity of Tax and Pak3. It will be of interest to determine whether CRTC2 and CRTC3 could account for the remaining ac tivity of Tax and Pak3 in the presence of CRTC1M1. Exactly how Paks affect the activity of CREB, CRTCs and p300CBP remains to be elucidated. promotion info In this regard, we showed that depletion of Pak1 suppressed the recruitment of Tax to the LTR. Because Tax is required for the recruitment and activation of CREB, CRTCs and p300CBP. the activity of these transcriptional regu lators should also be compromised in the absence of Paks. At least three additional lines of experiments are required Inhibitors,Modulators,Libraries to derive mechanistic insight on the transcriptional regula tory function of group I Paks.
First, the dispensability of the kinase domain for Inhibitors,Modulators,Libraries the augmentation of Tax activity should Inhibitors,Modulators,Libraries be determined. Second, the M5 mutant recruited to the promoter through Gal4BD should be assessed for transcriptional activity. Finally, possible involvement of CtBP and histone H3 phosphorylation in Pak augmented activation of HTLV 1 LTR by Tax should be investigated. Emerging evidence implicates group I Paks in supporting the replication of various human viruses. Thus, associ ation and activation of Pak2 Inhibitors,Modulators,Libraries by viral Nef protein were thought to play a role in HIV 1 replication. In addition, an RNAi screen identified Pak1 and Pak3 to be important host factors that support HIV 1 infection in HeLa cells and T lymphocytes.
On the other hand, hepatitis B virus oncoprotein HBx was recently shown to activate Pak1 to promote cell survival. Our findings that group I Paks facilitate HTLV 1 transcription are generally consistent with the notion that these Paks play an important role in the Inhibitors,Modulators,Libraries life cycle of human viruses of different families. Small molecule inhibitors of Paks are thought to be attractive therapeutic agents for different types of cancer and viruses. Be cause the facilitator function of Paks on Tax induced LTR activation is kinase independent, kinase inhibitors of Paks might not be useful in anti HTLV 1 therapy. However, pep tide mimetics that can inhibit the interaction between Paks and Tax would still hold the promise for the design and de velopment of new molecularly targeted anti HTLV 1 and anti ATL therapeutics.
Group I Paks are a critical regulatory point in cell signal ing on which diverse upstream signals converge. It remains to be understood how these sellectchem signals might affect the interaction between Tax and Paks. Tax appears to be able to promote the recruitment of Paks to HTLV I LTR. The mechanisms of this recruitment and the cellular factors that regulate this process warrant further investigations. Paks are frequently upregulated in cancer cells and virus infected cells.