Studies of human endogenous retroviruses and of the TGF-beta signaling pathway

Sammanfattning: The human genome, in common with all mammalian genomes, carries a high load of inheritable retroviral sequences. We have identified and characterized a novel family of these endogenous retroviruses and have named this family HERV-F as based on the primer binding sites of three members. The HERV-Fs are C-type endogenous retroviruses that have unique gag, pol and env regions that are, based on phylogenetic analyses, most closely related to the HERV-Hs. Southern blot analysis demonstrates that the HERV-Fs have at least 16 members in the human genome and that related elements exist not only in all Old World monkeys investigated but also in a New World monkey; this indicates an incorporation into the primate lineage some 50-60 million years ago. One member, designated HERV-F(XA34), is actively transcribed in human placental and fetal tissue. This element has a complex splicing pattern and the capacity to encode Gag protein. We have also investigated three other families of endogenous retroviruses, HERV-R, HERV-E and RRHERV-I and found in two families, indications of an over-representation of these elements on the Y-chromosome. Human gliomas are known to express high levels of TGF-b and consequently they seem to be resistant to the growth inhibitory effect of exogenous TGF-b. Using tumor material derived from glioma patients, we have investigated the mRNA expression of the TGF-b isoforms and components of the TGF-b signaling pathway. High-grade gliomas were found to express increased levels of TGF-b1, -2 and -3, as well as increased levels of TbRI and -II but decreased levels of Smads. We have also used high-density filter array technology to analyze the effects that the three isoforms of TGF-b have on gene transcription from monocytic cell lines and have found clear and differential effects between the three isoforms.