The regulatory mechanisms controlling entry and exit from the cell cycle appear to be important in development of neoplasia because this abnormality indicates an apparent lack of appropriate cell growth control. This may be the result of a lack of control in regulating exit from the cell cycle, through the action of tumor suppressor genes, or entry into the cell cycle through the action of the dominant oncogenes. One current model of cell cycle regulation holds that G1 phase represents a gateway during which cells either cease to proliferate before retiring from the cell cycle to differentiate, become quiescent or become committed to proceed through another cell cycle. While some of the components thought to regulate this system have been identified (eg.p34cdc2, RB105, G1 phase cyclins) many of the details remain enigmatic. Recently, a unique human G1 phase-specific cDNA (hG1.1) has been isolated from a subtractive cDNA library of lower abundance G1 phase transcripts. Transcription of this gene occurs during a very narrow window of time during G1 phase of both the continuous cell cycle and re-entry from quiescence. Therefore, this cDNA may represent a novel cell cycle regulator and may participate as part of the G1 phase gateway. The overall goal of the proposed research is to elucidate part of the mechanism regulating how a cell determines its response in G1 phase by characterizing the role of this G1 phase-specific transcript and correlating its function with those of other known G1 phase regulatory genes. The objectives of this research are designed to extend the cloning and further characterize the biological role of hG1.1. The cloning strategy employed selected for G1 phase-specific expression; however, further characterization is required to determine the role hG1.1 plays in the regulation of cell cycle progression. The specific objectives will determine what effect over and underexpression of hG1.1 have on normal cell cycle progression and if this effect is specific to a particular cell cycle phase. The specific objectives are: (1) Clone and sequence full length cDNA encoding the G1 phase-specific mRNA hG1.1, a human cell cycle phase- specific transcript, (2) Characterize the effects of unregulated overexpression of hG1.1 on cell cycle progression in transient and stable transfection assays, and (3) Characterize the effects of inhibition of hG1.1 expression on cell cycle progression by the use of antisense oligonucleotide feeding.
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