Differentiation linked regulation of telomerase activity by Makorin-1.
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.
Salvatico
Jose
J
Department of Molecular and Microbiology, College of Medicine, University of Central Florida, Orlando, FL 32826, USA.
Kim
Joo Hee
JH
Chung
In Kwon
IK
Muller
Mark T
MT
D015153:Blotting, Western; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism
C410808:Makorin ring finger protein 1; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D012261:Ribonucleoproteins; C509186:TERT protein, human; D019098:Telomerase
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