Progesterone Receptors Induce Cell Cycle Progression via Activation of Mitogen-Activated Protein Kinases

Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-x L by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies.

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Regulation of cyclin D1 expression and cell cycle progression by mitogen-activated protein kinase cascade

Kidney International ◽

10.1046/j.1523-1755.1999.00704.x ◽

1999 ◽

Vol 56 (4) ◽

pp. 1258-1261 ◽

Cited By ~ 38

Author(s):

Yoshio Terada ◽

Seiji Inoshita ◽

Osamu Nakashima ◽

Michio Kuwahara ◽

Sei Sasaki ◽

...

Keyword(s):

Cell Cycle ◽

Protein Kinase ◽

Cyclin D1 ◽

Cell Cycle Progression ◽

Mitogen Activated Protein Kinase ◽

Cycle Progression ◽

Mitogen Activated Protein ◽

Kinase Cascade ◽

Protein Kinase Cascade

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Cell Cycle Arrest and Reversion of Ras-Induced Transformation by a Conditionally Activated Form of Mitogen-Activated Protein Kinase Kinase Kinase 3

Molecular and Cellular Biology ◽

10.1128/mcb.19.5.3857 ◽

1999 ◽

Vol 19 (5) ◽

pp. 3857-3868 ◽

Cited By ~ 57

Author(s):

Heidrun Ellinger-Ziegelbauer ◽

Kathleen Kelly ◽

Ulrich Siebenlist

Keyword(s):

Cell Cycle ◽

Protein Kinase ◽

Cyclin D1 ◽

Stress Responses ◽

Cell Cycle Progression ◽

Cellular Transformation ◽

Mitogen Activated Protein Kinase ◽

Cycle Progression ◽

Mapk Kinase ◽

Mitogen Activated Protein

ABSTRACT Signal-induced proliferation, differentiation, or stress responses of cells depend on mitogen-activated protein kinase (MAPK) cascades, the core modules of which consist of members of three successively acting kinase families (MAPK kinase kinase [MAP3K], MAPK kinase, and MAPK). It is demonstrated here that the MEKK3 kinase inhibits cell proliferation, a biologic response not commonly associated with members of the MAP3K family of kinases. A conditionally activated form of MEKK3 stably expressed in fibroblasts arrests these cells in early G1. MEKK3 critically blocks mitogen-driven expression of cyclin D1, a cyclin which is essential for progression of fibroblasts through G1. The MEKK3-induced block of cyclin D1 expression and of cell cycle progression may be mediated via p38 MAPK, a downstream effector of MEKK3. The MEKK3-mediated block of proliferation also reverses Ras-induced cellular transformation, suggesting possible tumor-suppressing functions for this kinase. Together, these results suggest an involvement of the MEKK3 kinase in negative regulation of cell cycle progression, and they provide the first insights into biologic activities of this kinase.

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