Title

Differentiation Linked Regulation Of Telomerase Activity By Makorin-1

Keywords

hTERT; Makorin-1; Proteasome; Telomerase; Ubiquitin; Ubiquitin ligase

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. © 2010 Springer Science+Business Media, LLC.

Publication Date

9-1-2010

Publication Title

Molecular and Cellular Biochemistry

Volume

342

Issue

1-2

Number of Pages

241-250

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1007/s11010-010-0490-x

Socpus ID

77955852573 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/77955852573

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