Biomaterial Database

Nuclear import of hTERT requires a bipartite nuclear localization signal and Akt-mediated phosphorylation. 2012

Jeeyun Chung, and Prabhat Khadka, and In Kwon Chung

Department of Systems Biology, Yonsei University, Seoul, Korea.

Sustained cell proliferation requires telomerase to maintain functional telomeres that are essential for chromosome integrity and protection. Although nuclear import of telomerase transcriptase (hTERT) is required for telomerase activity to elongate telomeres in vivo, the molecular mechanism regulating nuclear localization of hTERT is unclear. We have identified a bipartite nuclear localization signal (NLS; amino acid residues 222-240) that is responsible for nuclear import of hTERT. Immunofluorescence imaging of hTERT revealed that mutations in any of the bipartite NLS sequences result in decreased nuclear fluorescence intensity compared with wild-type hTERT. We also show that Akt-mediated phosphorylation at serine 227 is necessary for directing nuclear translocation of hTERT. Interestingly, serine 227 is located between two clusters of basic amino acids in the bipartite NLS. Inactivation of Akt activity by a dominant-negative mutant or wortmannin treatment attenuated nuclear localization of hTERT. We further show that both bipartite NLS and serine 227 in hTERT are required for cell immortalization of normal human foreskin fibroblast cells. Taken together, our findings reveal a previously unknown regulatory mechanism for nuclear import of hTERT through a bipartite NLS mediated by Akt phosphorylation, which represents an alternative pathway for modulating telomerase activity in cancer.

UI	MeSH Term	Description	Entries
D008297	Male		Males
D008969	Molecular Sequence Data	Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.	Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D009154	Mutation	Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.	Mutations
D010766	Phosphorylation	The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.	Phosphorylations
D010768	Phosphoserine	The phosphoric acid ester of serine.	Serine Phosphate,Phosphorylserine,Seryl Phosphate,Phosphate, Serine,Phosphate, Seryl
D002461	Cell Line, Transformed	Eukaryotic cell line obtained in a quiescent or stationary phase which undergoes conversion to a state of unregulated growth in culture, resembling an in vitro tumor. It occurs spontaneously or through interaction with viruses, oncogenes, radiation, or drugs/chemicals.	Transformed Cell Line,Cell Lines, Transformed,Transformed Cell Lines
D002467	Cell Nucleus	Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)	Cell Nuclei,Nuclei, Cell,Nucleus, Cell
D005347	Fibroblasts	Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.	Fibroblast
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000595	Amino Acid Sequence	The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.	Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein