Regulation of the G2/M transition by p53.
William R Taylor,George R. Stark +1 more
TLDR
Evidence that implicates p53 in controlling entry into mitosis when cells enter G2 with damaged DNA or when they are arrested in S phase due to depletion of the substrates required for DNA synthesis is reviewed.Abstract:
p53 protects mammals from neoplasia by inducing apoptosis, DNA repair and cell cycle arrest in response to a variety of stresses. p53-dependent arrest of cells in the G1 phase of the cell cycle is an important component of the cellular response to stress. Here we review recent evidence that implicates p53 in controlling entry into mitosis when cells enter G2 with damaged DNA or when they are arrested in S phase due to depletion of the substrates required for DNA synthesis. Part of the mechanism by which p53 blocks cells at the G2 checkpoint involves inhibition of Cdc2, the cyclin-dependent kinase required to enter mitosis. Cdc2 is inhibited simultaneously by three transcriptional targets of p53, Gadd45, p21, and 14-3-3σ. Binding of Cdc2 to Cyclin B1 is required for its activity, and repression of the cyclin B1 gene by p53 also contributes to blocking entry into mitosis. p53 also represses the cdc2 gene, to help ensure that cells do not escape the initial block. Genotoxic stress also activates p53-independent pathways that inhibit Cdc2 activity, activation of the protein kinases Chk1 and Chk2 by the protein kinases Atm and Atr. Chk1 and Chk2 inhibit Cdc2 by inactivating Cdc25, the phosphatase that normally activates Cdc2. Chk1, Chk2, Atm and Atr also contribute to the activation of p53 in response to genotoxic stress and therefore play multiple roles. p53 induces transcription of the reprimo, B99, and mcg10 genes, all of which contribute to the arrest of cells in G2, but the mechanisms of cell cycle arrest by these genes is not known. Repression of the topoisomerase II gene by p53 helps to block entry into mitosis and strengthens the G2 arrest. In summary, multiple overlapping p53-dependent and p53-independent pathways regulate the G2/M transition in response to genotoxic stress.read more
Citations
More filters
Journal ArticleDOI
Cell-cycle checkpoints and cancer
Michael B. Kastan,Jiri Bartek +1 more
TL;DR: All life on earth must cope with constant exposure to DNA-damaging agents such as the Sun's radiation, and how cells respond to DNA damage are critical determinants of whether that individual will develop cancer.
Journal ArticleDOI
p21 in cancer: intricate networks and multiple activities
Tarek Abbas,Anindya Dutta +1 more
TL;DR: This Review focuses on recent advances in the understanding of the regulation of p21 and its biological functions with emphasis on its p53-independent tumour suppressor activities and paradoxical tumour-promoting activities, and their implications in cancer.
Journal ArticleDOI
Cellular response to oxidative stress: signaling for suicide and survival.
TL;DR: The various signaling pathways known to be activated in response to oxidative stress in mammalian cells, the mechanisms leading to their activation, and their roles in influencing cell survival are discussed.
Journal ArticleDOI
The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer
TL;DR: This review provides an overview of deregulation of the cell cycle in cancer by focusing on mechanisms, i.e. regulation of cyclin‐dependent kinases (CDK) by cyclins, CDK inhibitors and phosphorylating events.
Journal ArticleDOI
The history and future of targeting cyclin-dependent kinases in cancer therapy
TL;DR: How CDK inhibitors with high selectivity (particularly for both CDK4 and CDK6), in combination with patient stratification, have resulted in more substantial clinical activity is discussed.
References
More filters
Journal Article
Participation of p53 Protein in the Cellular Response to DNA Damage
TL;DR: A role for the wild-type p53 protein in the inhibition of DNA synthesis that follows DNA damage is suggested and a new mechanism for how the loss of wild- type p53 might contribute to tumorigenesis is suggested.
Journal ArticleDOI
Checkpoints: controls that ensure the order of cell cycle events
Leland H. Hartwell,Ted Weinert +1 more
TL;DR: It appears that some checkpoints are eliminated during the early embryonic development of some organisms; this fact may pose special problems for the fidelity of embryonic cell division.
Journal ArticleDOI
Requirement for p53 and p21 to Sustain G2 Arrest After DNA Damage
Fred Bunz,A. Dutriaux,Christoph Lengauer,Todd Waldman,Shibin Zhou,J. P. Brown,John M. Sedivy,Kenneth W. Kinzler,Bert Vogelstein +8 more
TL;DR: After DNA damage, many cells appear to enter a sustained arrest in the G2 phase of the cell cycle but this arrest could be sustained only when p53 was present in the cell and capable of transcriptionally activating the cyclin-dependent kinase inhibitor p21.
Journal ArticleDOI
Universal control mechanism regulating onset of M-phase
TL;DR: The onset of M-phase is regulated by a mechanism common to all eukaryotic cells and requires p34cdc2 dephosphorylation and association with cyclin.
Journal ArticleDOI
T Antigen Is Bound to a Host Protein in Sv40-Transformed Cells
TL;DR: It is reported here that the T antigen in a line of SV40-transformed mouse cells forms an oligomeric complex with a specific cell coded protein.