Induction of senescence-like phenotypes by forced expression of hic-5, which encodes a novel LIM motif protein, in immortalized human fibroblasts.
The hic-5 gene encodes a novel protein with Zn finger-like (LIM) motifs, the expression of which increases during cellular senescence. The ectopic expression of hic-5 in nontumorigenic immortalized human fibroblasts, whose expression levels of hic-5 were significantly reduced in comparison with those of mortal cells, decreased colony-forming efficiency. Stable clones expressing high levels of hic-5 mRNA showed higher levels of mRNAs for several extracellular matrix-related proteins, along with the alteration of an alternative splicing as seen in senescent cells and decreased c-fos inducibility. Furthermore, these clones acquired a senescence-like phenotype, such as growth retardation; senescence-like morphology; and increased expression of Cip1/WAF1/sdi1 after 20 to 40 population doublings. On the other hand, antisense RNA expression of hic-5 in human normal diploid fibroblasts delayed the senescence process. HIC-5 was localized in nuclei and had affinity for DNA. Based on these observations, we speculated that HIC-5 affected the expression of senescence-related genes through interacting with DNA and thereby induced the senescence-like phenotypes. To our knowledge, hic-5 is the first single gene that could induce senescence-like phenotypes in a certain type of immortalized human cell and mediate the normal process of senescence.
Shibanuma
M
M
Department of Microbiology, Showa University School of Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan.
Mochizuki
E
E
Maniwa
R
R
Mashimo
J
J
Nishiya
N
N
Imai
S
S
Takano
T
T
Oshimura
M
M
Nose
K
K
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D016922:Cellular Senescence / Q000235:genetics; D017364:Collagenases / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D003598:Cytoskeletal Proteins; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology*; D005353:Fibronectins / Q000235:genetics; D015870:Gene Expression; D016762:Genes, fos / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D051379:Mice; D008969:Molecular Sequence Data; D010641:Phenotype; D016372:RNA, Antisense / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D016335:Zinc Fingers
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D005353:Fibronectins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D016372:RNA, Antisense; D012333:RNA, Messenger; C490351:TGFB1I1 protein, human; C090090:Tgfb1i1 protein, mouse; D004247:DNA; D017364:Collagenases