Identification of a G1-S-phase-regulated region in the human thymidine kinase gene promoter.

Roehl, Holger; Conrad, Susan E.

doi:10.1128/mcb.10.7.3834

Cited by 45 publications

(41 citation statements)

References 19 publications

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“…A region between -139 and -88 showed the most dramatic decrease, of about 2.5-fold. Further 5' deletion studies in the context of the homologous TK promoter revealed that deletion to -83 and -64 resulted in superinducibility of the TK transcripts by cycloheximide (23) and that deletion of the TK sequence from -135 to -67 resulted in the loss of G1-S-phase regulation (28). Our results demonstrated that the same region (-133 to -64) is likely to contain a CCRU for the TK promoter.…”

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confidence: 62%

Identification of a 70-base-pair cell cycle regulatory unit within the promoter of the human thymidine kinase gene and its interaction with cellular factors.

Kim¹,

Lee²

1991

Mol. Cell. Biol.

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The promoter of the human thymidine kinase gene contains cis-regulatory elements responsible for its cell-cycle-regulated expression. We report here that a 70-bp region between -133 and -64 is sufficient to confer cell cycle regulation on a heterologous promoter. The 20-bp region between -64 and -83, which contains an inverted CCAAT motif, is important for transcriptional stimulation of this functional unit. The sequence of this CCAAT motif is nearly identical to the consensus sequence for the transcriptional factor CP1. We also examined the specificity and binding activities of cellular factors interacting with the 70-bp fragment.We showed that the cellular factors binding to the 70-bp region are similar during the Gl, S, and G2 phases, suggesting that the cell cycle regulatory activity observed must involve processes other than factor binding to the DNA.The thymidine kinase (TK) gene encodes a cytosolic enzyme of the pyrimidine salvage pathway. This enzyme catalyzes the phosphorylation of thymidine to form thymidine 5'-monophosphate. Its activity is maximal during the onset of DNA synthesis in the mammalian cell cycle (18). In growth-arrested quiescent cells and terminally differentiated postreplicative cells, the TK activity is diminished and the TK gene is transcriptionally repressed (11,29).To understand the mechanism whereby the TK gene is temporally regulated during the cell cycle, the levels of control of the TK gene have been investigated. It has been established that the TK gene is regulated at both the transcriptional and the posttranscriptional levels. With the onset of DNA synthesis, there is a severalfold increase in the rate of transcription of the TK gene (6,32). At the same time, there is a change in the nuclear posttranscriptional processing of TK heterogeneous nuclear RNA (12). The steady-state levels of TK mRNA also increase sharply as the cells enter the S phase (24). Thus, several mechanisms might contribute to the 10-to 20-fold increase in the TK mRNA levels during the DNA synthetic phase of the cell cycle.The direct observation that the TK gene is transcriptionally activated at the border of the G1 and S phases suggests that sequences contained within the promoter of the TK gene might direct the increase in its transcription rate during the cell cycle. To establish the existence of such a sequence, we and others fused the TK promoter sequence to reporter genes such as the neomycin resistance gene (neo) and the chloramphenicol acetyltransferase (CAT) gene and monitored their expression during the cell cycle (17, 33). In both reporter gene systems, cell cycle regulation was observed. These results provide the first evidence that the TK promoter sequence is capable of directing cell cycle regulation of heterologous genes. Deletion analysis revealed that the region important for cell cycle regulation is between -441 and -64 bp from the transcriptional start site. We also demonstrated that this 378-bp TK promoter fragment has * Corresponding author. enhancing activity and can confer cell cy...

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confidence: 62%

Identification of a 70-base-pair cell cycle regulatory unit within the promoter of the human thymidine kinase gene and its interaction with cellular factors.

Kim¹,

Lee²

1991

Mol. Cell. Biol.

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“…A significant correlation between TK1 in breast tumors determined by immunohistochemistry and Ki-67 labeling index (Ki-67 LI) has been reported by He et al (9). The activity of TK1 is S phase-specific (10)(11)(12)(13), it increases in S phase (14) and is targeted for degradation in late M phase (15)(16)(17)(18), such that newly divided G 1 cells have low TK1 levels (19). Our group has shown that TK1 and cofactor, ATP, regulate […”

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confidence: 99%

Quantification of Cellular Proliferation in Tumor and Normal Tissues of Patients with Breast Cancer by [18F]Fluorothymidine-Positron Emission Tomography Imaging: Evaluation of Analytical Methods

Kenny¹,

et al. 2005

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There is an unmet need to develop imaging methods for the early and objective assessment of breast tumors to therapy. 18 F]FLT (K i ) ranged from 0.6 to 10.4 Â 10 À4 and from 0 to 0.6 Â 10 À4 mL plasma cleared/s/mL tissue in tumor (29 regions, 15 patients) and normal tissues, respectively. Tumor K i and fractional retention of radiotracer determined by spectral analysis correlated with Ki-67 labeling index (r = 0.92, P < 0.0001 and r = 0.92, P < 0.0001, respectively). These correlations were superior to those determined by semiquantitative methods. We conclude that [ 18 F]FLT-positron emission tomography is a promising clinical tool for imaging cellular proliferation in breast cancer, and is most predictive when analyzed by graphical and spectral methods. (Cancer Res 2005; 65(21): 10104-12)

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“…Using deletion and site-directed mutational analysis, it was established that the upstream sequences of the human TK promoter, spanning nucleotides Ϫ133 to Ϫ64, designated CCRU (cell cycle regulatory unit), were sufficient to confer cell cycle regulation (23,24). Furthermore, this 70-bp CCRU domain is able to confer G 1 -S regulation onto a non-cell cycle-regulated, heterologous promoter (24).…”

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confidence: 99%

Constitutive Protection of E2F Recognition Sequences in the Human Thymidine Kinase Promoter during Cell Cycle Progression

Tommasi

Pfeifer

1997

Journal of Biological Chemistry

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Identification of a G1-S-phase-regulated region in the human thymidine kinase gene promoter.

Cited by 45 publications

References 19 publications

Identification of a 70-base-pair cell cycle regulatory unit within the promoter of the human thymidine kinase gene and its interaction with cellular factors.

Identification of a 70-base-pair cell cycle regulatory unit within the promoter of the human thymidine kinase gene and its interaction with cellular factors.

Quantification of Cellular Proliferation in Tumor and Normal Tissues of Patients with Breast Cancer by [18F]Fluorothymidine-Positron Emission Tomography Imaging: Evaluation of Analytical Methods

Constitutive Protection of E2F Recognition Sequences in the Human Thymidine Kinase Promoter during Cell Cycle Progression

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