Cell cycle regulation of the cyclin A, cdc25C and cdc2 genes is based on a common mechanism of transcriptional repression.

Abstract In B-cell chronic lymphocytic leukemia (B-CLL), malignant cells seem to be arrested in the G0/early G1phase of the cell cycle, and defective apoptosis might be involved in disease progression. However, increasing evidence exists that B-CLL is more than a disease consisting of slowly accumulating resting B cells: a proliferating pool of cells has been described in lymph nodes and bone marrow and might feed the accumulating pool in the blood. Rapamycin has been reported to inhibit cell cycle progression in a variety of cell types, including human B cells, and has shown activity against a broad range of human tumor cell lines. Therefore, we investigated the ability of rapamycin to block cell cycle progression in proliferating B-CLL cells. We have recently demonstrated that stimulation with CpG-oligonucleotides and interleukin-2 provides a valuable model for studying cell cycle regulation in malignant B cells. In our present study, we demonstrated that rapamycin induced cell cycle arrest in proliferating B-CLL cells and inhibited phosphorylation of p70s6 kinase (p70s6k). In contrast to previous reports on nonmalignant B cells, the expression of the cell cycle inhibitor p27 was not changed in rapamycin-treated leukemic cells. Treatment with rapamycin prevented retinoblastoma protein (RB) phosphorylation in B-CLL cells without affecting the expression of cyclin D2, but cyclin D3 was no longer detectable in rapamycin-treated B-CLL cells. In addition, rapamycin treatment inhibited cyclin-dependent kinase 2 activity by preventing up-regulation of cyclin E and cyclin A. Interestingly, survivin, which is expressed in the proliferation centers of B-CLL patients in vivo, is not up-regulated in rapamycin-treated cells. Therefore, rapamycin interferes with the expression of many critical molecules for cell cycle regulation in cycling B-CLL cells. We conclude from our study that rapamycin might be an attractive substance for therapy for B-CLL patients by inducing a G1 arrest in proliferating tumor cells.

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Cell-cycle regulation of gene expression by transcriptional repression

Trends in Genetics ◽

10.1016/s0168-9525(96)30112-1 ◽

1997 ◽

Vol 13 (1) ◽

pp. 3-6 ◽

Cited By ~ 73

Author(s):

Jörk Zwicker ◽

Rolf Müller

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Transcriptional Repression ◽

Cell Cycle Regulation ◽

Regulation Of Gene Expression ◽

Cycle Regulation

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Cell cycle regulation of the E2F transcription factor involves an interaction with cyclin A

Cell ◽

10.1016/0092-8674(91)90019-u ◽

1991 ◽

Vol 65 (7) ◽

pp. 1243-1253 ◽

Cited By ~ 165

Author(s):

Maria Mudryj ◽

Stephen H. Devoto ◽

Scott W. Hiebert ◽

Tony Hunter ◽

Jonathon Pines ◽

...

Keyword(s):

Cell Cycle ◽

Transcription Factor ◽

Cell Cycle Regulation ◽

Cyclin A ◽

E2f Transcription Factor ◽

Cycle Regulation

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The Transcriptional Repressor HBP1 Is a Target of the p38 Mitogen-Activated Protein Kinase Pathway in Cell Cycle Regulation

Molecular and Cellular Biology ◽

10.1128/mcb.23.23.8890-8901.2003 ◽

2003 ◽

Vol 23 (23) ◽

pp. 8890-8901 ◽

Cited By ~ 39

Author(s):

Mei Xiu ◽

Jiyoung Kim ◽

Ellen Sampson ◽

Chun-Yin Huang ◽

Roger J. Davis ◽

...

Keyword(s):

Cell Cycle ◽

Map Kinase ◽

Transcriptional Repression ◽

Cell Cycle Regulation ◽

Phosphorylation Site ◽

P38 Map Kinase ◽

Protein Levels ◽

Mitogen Activated Protein ◽

Protein Instability ◽

Cycle Regulation

ABSTRACT The p38 mitogen-activated protein (MAP) kinase signaling pathway participates in both apoptosis and G1 arrest. In contrast to the established role in apoptosis, the documented induction of G1 arrest by activation of the p38 MAP kinase pathway has attracted recent attention with reports of substrates that are linked to cell cycle regulation. Here, we identify the high-mobility group box protein HBP1 transcriptional repressor as a new substrate for p38 MAP kinase. Our previous work had shown that HBP1 inhibits G1 progression in cell and animal models, and thus indicated that HBP1 could be a relevant substrate for p38 MAP kinase in cell cycle regulation. In the present work, a p38 MAP kinase docking site (amino acids [aa] 81 to 125) and a p38 MAP kinase phosphorylation site (serine 401) were identified in the HBP1 protein. Furthermore, the docking and phosphorylation sites on HBP1 were specific for p38 MAP kinase. In defining the role of p38 MAP kinase regulation, the inhibition of p38 MAP kinase activity was shown to decrease HBP1 protein levels by triggering protein instability, as manifested by a decrease in protein half-life. Consistently, a decrease in protein levels was accompanied by a decrease in overall DNA binding activity. A mutation of the p38 MAP kinase phosphorylation site at aa 401 [(S-A)401HBP1] also triggered HBP1 protein instability. While protein stability was compromised by mutation, the specific activities of (S-A)401HBP1 and of wild-type HBP1 appeared comparable for transcriptional repression. This comparison of transcription-specific activity highlighted that p38 MAP kinase regulated HBP1 protein levels but not the intrinsic activity for DNA binding or for transcriptional repression. Finally, p38 MAP kinase-mediated regulation of the HBP1 protein also contributed to the regulation of G1 progression. Together, our work supports a molecular framework in which p38 MAP kinase activity contributes to cell cycle inhibition by increasing HBP1 and other G1 inhibitory factors by regulating protein stability.

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