Endogenous reverse transcriptase: a mediator of cell proliferation and differentiation

Abstract

Endogenous, non-telomeric Reverse Transcriptase (RT) is encoded by two classes of repeated genomic elements, retrotransposons and endogenous retroviruses, and is an essential component of the retrotransposition machinery of both types of elements. Expression of RT-coding genes is generally repressed in non-pathological, terminally differentiated cells, but is active in early embryos, germ cells, embryo and tumor tissues, all of which have a high proliferative potential. To clarify whether reverse transcription is functionally implicated in control of cell growth, differentiation and in embryogenesis, recent experiments have been undertaken to inactivate the endogenous RT activity. RT was inhibited in normal and transformed cell lines by exposure to nevirapine, a non-nucleosidic RT inhibitor. The endogenous RT was also blocked in murine embryos by microinjection of an anti-RT antibody. Both experimental approaches yielded a dramatic inhibition of proliferation. Murine embryos arrested at pre-implantation stages. Transformed cell lines underwent a significant reduction in the rate of cell growth, concomitant with the induction of differentiation. In addition, RT inhibition induced an extensive reprogramming of the gene expression profile both in cultured cell lines and in preimplantation embryos. From these studies, endogenous RT begins to emerge as a key function with a driving role in normal and pathological developmental processes.

Reverse transcriptase activity associated with haemic neoplasia in the soft-shell clam Mya arenaria

“…Further supporting our contention of an endogenous source of RT is the report that RT-coding genes are generally active in cancer cells (Spadafora 2004). In addition, RT gene activity is up-regulated by a variety of stimuli acting at the genomewide level such as cellular stress, heat shock, genotoxic agents and others (Sciamanna et al 2005).…”

“…Our suggestion is supported by the growing body of data showing that transformed cells of mammalian origin express high levels of endogenous non-telomeric RT, with the source of the RT being endogenous retroelements (Spadafora 2004, Oricchio et al 2007). Involvement of endogenous retrovirus in HN of Mya arenaria was previously suggested by Oprandy & Chang (1983).…”

“…in turtles (Casey et al 1997), humans (Molès et al 2007), and cockles (Romalde et al 2007). The observed RT activity in HN-negative clams could be related to the fact that RT activity is associated with a wide range of biological processes, both physiological and pathological (Spadafora 2004). This is because RT-coding genes are also contained in repeated genomic elements called retroelements, which play an important role in many physiological and pathological cellular processes (Spadafora 2004).…”

“…Moreover, RT-related sequences are found in cellular genomes generally known as retroelements (Flint et al 2004). Expression of these endogenous cellular RT-coding genes is repressed in normal terminally differentiated cells, but can be active in tissues with rapidly dividing cells such as germ cells, embryos, and tumors (Spadafora 2004).…”

Reverse transcriptase inhibitors induce cell differentiation and enhance the immunogenic phenotype in human renal clear‐cell carcinoma

“…8,13 Indeed, endogenous RT is encoded by retro-transposable elements, such as LINE1, and endogenous retroviruses, 14 and its expression is highly upregulated in embryonic tissues and undifferentiated cells [15][16][17] as well as in tumors, 18,19 whereas it is silenced in differentiated, nonpathological tissues. Consistently, the silencing of RT-encoding LINE-1 elements by RNA interference or the pharmacological inhibition of endogenous RT activity results in a reversible decrease in the rate of cell growth and in the induction of cell differentiation in several human tumor cell lines such as breast, colon, lung, prostate, thyroid carcinoma and melanoma cells.…”