Cell cycle regulation by HIF-1α and HIF-2α

Constantinos Demonacos, Muhammad Atif Chaudhry

    Research output: ThesisMaster's Thesis

    Abstract

    Cell cycle is an essential process of the cellular life as it provides the ability to the cell to produce exact replicas of itself. This process has to be performed with high accuracy for cells, tissues and organisms to propagate properly. The molecular machinery responsible for the precision and correct timing of the cell cycle consists of a network of signalling molecules that ensure tight regulation of mitotic cell cycle progression. Lack of fidelity and imprecision in the replication of genomic DNA will give rise to the propagation of defective cells, which is a significant factor contributing to the development of malignancies in eukaryotes. The order of the cell cycle events is controlled by intracellular checkpoints occurring at G1/S phase boundary, in S and G2/M phases. Important role in these checkpoints is exerted by the p27Kip1 and p57Kip2 cyclin dependent kinase (CDK) inhibitors, which arrest cell growth between G1 and S phase giving the opportunity to the cells to repair cellular damages or undergo cellular death in case the damage is not repairable. Oxygen deprivation or hypoxia where the oxygen supply is below the required level is a common characteristic of tumours and it is considered to be a fundamental regulator of carcinogenesis. The transcription factor Hypoxia-Inducible Factor 1alpha (HIF-1α) is a key regulatory feature of hypoxic cells coordinating several signalling pathways under hypoxic conditions to modulate tumour cell growth and metastasis. The HIF-1α homologue HIF-2α is expressed in a tissue-specific manner stimulating variable gene expression of HIF-1α transcription targets and the HIF-2α dependent induction of the expression of these genes occurs in normoxia. The differences in the function of HIF-1α and HIF-2α led to the hypothesis that the diverse effects on cell cycle exerted by these two HIF-α homologues might be a result of the differential induction of the expression of the p27Kip1 and p57Kip2 CDK inhibitors mediated by the two transcription factors. Understanding the molecular mechanisms employed by HIF-1α and HIF-2α, which are two major factors involved in tumourigenesis might offer important clues as to the determinants of normal versus abnormal proliferation and provide the means for the development of novel anticancer therapeutics.
    Original languageEnglish
    Awarding Institution
    Publisher
    Publication statusPublished - Dec 2009

    Keywords

    • Transcription
    • Cancer
    • Cell cycle regulation
    • Hypoxia Inducible Factor 1 alpha (HIF-1alpha),
    • Hypoxia Inducible Factor 2 alpha (HIF-2alpha)
    • Cell cycle dependent kinase (CDK) inhibitor p27Kip1
    • Cell cycle dependent kinase (CDK) inhibitor p57Kip2

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