Perspectives in cell cycle regulation: lessons from an anoxic vertebrate

Abstract

The ability of an animal, normally dependent on aerobic respiration, to suspend breathing and enter an anoxic state for long term survival is clearly a fascinating feat, and has been the focus of numerous biochemical studies. When anoxia tolerant turtles are faced with periods of oxygen deprivation, numerous physiological and biochemical alterations take place in order to facilitate vital reductions in ATP consumption. Such strategies include reversible post-translational modifications as well as the implementation of translation and transcription controls facilitating metabolic depression. Although it is clear that anoxic survival relies on the suppression of ATP consuming processes, the state of the cell cycle in anoxia tolerant vertebrates remain elusive. Several anoxia tolerant invertebrate and embryonic vertebrate models display cell cycle arrest when presented with anoxic stress. Despite this, the cell cycle has not yet been characterized for anoxia tolerant turtles. Understanding how vertebrates respond to anoxia can have important clinical implications. Uncontrollable cellular proliferation and hypoxic tumor progression are inescapably linked in vertebrate tissues. Consequentially, the molecular mechanisms controlling these processes have profound clinical consequences. This review article will discuss the theory of cell cycle arrest in anoxic vertebrates and more specifically, the control of the retinoblastoma pathway, the molecular markers of cell cycle arrest, the activation of checkpoint kinases, and the possibility of translational controls implemented by microRNAs.

Keywords: Cell cycle; Trachemys scripta elegans.; anoxia tolerance; chromatin remodeling; ischemia; microRNA; retinoblastoma.

Fig. (1)

The Rb:E2F pathway. Sequential phosphorylation by kinase complexes Cyclin D:Cdk 4/6 and Cyclin E:Cdk 2, respectively, causes conformational changes to the Rb structure and release of E2F. The release of E2F is necessary for the expression of S-phases genes.

Fig. (2)

Expression profiles of Cyclin:Cdk complexes throughout the cell cycle. Cyclic expression of these complexes allow for the completion of one phase before the initiation of the subsequent phase [107].

Fig. (3)

The ATM/ATR DNA damage response pathway and its downstream effectors leading to either G₁/S or G₂/M phase arrest.

Fig. (4)

Mechanism of Cdk activation involving regulatory phosphorylation and Cyclin binding.

Fig. (5)

Chromatin remodeling complexes associated with the Rb family. Complex composition changes with the duration and type of cell cycle arrest. Pictured are the complex members in A) cells undergoing general G₁ arrest and B) cells undergoing a reversible exit from the cell cycle (quiescence) [108].

Fig. (6)

MicroRNA biogenesis. Primary transcripts are transcribed by RNA polymerase II and excised by a series of riboendonucleases into single-stranded mature microRNA stuctures. Mature microRNA structures are then loaded into the microRNA induced silencing complex (miRISC) and represses translation of targeted mRNA through 3- UTR binding.