Differentiation linked regulation of telomerase activity by Makorin-1

    Authors

    J. Salvatico; J. H. Kim; I. K. Chung;M. T. Muller

    Comments

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    Abbreviated Journal Title

    Mol. Cell. Biochem.

    Keywords

    Makorin-1; hTERT; Ubiquitin; Ubiquitin ligase; Telomerase; Proteasome; BREAST-CANCER CELLS; REVERSE-TRANSCRIPTASE; LEUKEMIA-CELLS; CELLULAR-DIFFERENTIATION; EPIGENETIC REGULATION; ACTIVATES TELOMERASE; HTERT GENE; PROTEIN; EXPRESSION; MECHANISMS; Cell Biology

    Abstract

    To understand telomere homeostasis, a significant aspect of cancer and growth control, it is important to examine telomerase induction as well as mechanisms of regulated elimination. Makorin-1 (MKRN1) was previously shown to be an E3 ubiquitin ligase that targets the telomerase catalytic subunit (hTERT) for proteasome processing (Kim et al., Genes Dev 19:776-781, 2005). In this study we examined expression and regulation of endogenous MKRN1 during the cell cycle and terminal differentiation. When WI-38 cells transition from active growth into a resting G1 state, basal levels of MKRN1 were found to increase by sixfold. In contrast, cancer cells typically contained low or in some cases undetectable levels of MKRN1 protein. HL-60 cells growing exponentially in culture contain no detectable MKRN1; however, following terminal differentiation, MKRN1 mRNA and protein levels are strongly up-regulated while hTERT mRNA, hTERC, and telomerase are shut down. The initial decrease in telomerase activity is due to a gradual reduction in transcription of the hTERT gene that occurs during the first 12 h of terminal differentiation. MKRN1 protein appears between 12 and 24 h and is attended by a more rapid loss of telomerase activity. As more MKRN1 protein accumulates, significantly less telomerase activity is seen. Addition of the proteasome inhibitor, MG132, reverses the loss of telomerase activity; therefore, reductions in telomerase activity are dynamic, ongoing, and correlated with robust up-regulation of MKRN1 as the cells terminally differentiate. The data are consistent with the idea that MKRN1 represents a telomerase elimination pathway to rapidly draw down the activity during differentiation or cell cycle arrest when telomerase action at chromosome ends is no longer necessary.

    Journal Title

    Molecular and Cellular Biochemistry

    Volume

    342

    Issue/Number

    1-2

    Publication Date

    1-1-2010

    Document Type

    Article

    Language

    English

    First Page

    241

    Last Page

    250

    WOS Identifier

    WOS:000281054900028

    ISSN

    0300-8177

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