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Increased transcription and modified growth state‐dependent expression of the plasminogen activator inhibitor type‐1 gene characterize the senescent phenotype in human diploid fibroblasts
Author(s) -
Mu XiaoChun,
StaianoCoico Lisa,
Higgins Paul J.
Publication year - 1998
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/(sici)1097-4652(199801)174:1<90::aid-jcp10>3.0.co;2-s
Subject(s) - biology , plasminogen activator , gene expression , messenger rna , plasminogen activator inhibitor 1 , microbiology and biotechnology , gene , endocrinology , genetics
Abstract The type‐1 inhibitor of plasminogen activator (PAI‐1) is a major physiologic regulator of pericellular proteolytic activity and, as such, influences matrix integrity, cell‐to‐substrate adhesion, and cellular proliferation. Excessive accumulation of both PAI‐1 mRNA and protein correlates with the progressive acquisition of morphological and growth traits characteristic of the senescent phenotype (Mu and Higgins, 1995, J. Cell. Physiol., 165:647–657). Compared to early‐passage IMR‐90 human diploid fibroblasts, a late‐passage senescence‐associated 11‐fold elevation in steady‐state PAI‐1 mRNA content reflected a 15‐fold increase in constitutive PAI‐1 gene transcription. Differential mRNA stability was not a factor in age‐associated PAI‐1 overexpression in IMR‐90 cells. Upon removal of serum, early‐passage human fibroblasts enter into a state of growth arrest with marked down‐regulation of PAI‐1 synthesis. Rapid induction of both the 3.0‐ and 2.2‐kb PAI‐1 mRNA species was evident upon serum‐induced “activation” of quiescent early‐passage fibroblasts; induced PAI‐1 transcripts were maximal at 2 hr post‐serum stimulation and declined in late G 1 prior to entry into S phase. In contrast, late‐passage (p32) fibroblasts maintained a significant level of PAI‐1 expression under serum‐free culture conditions. Although the PAI‐1 gene was further responsive to serum in senescent cells, transcript abundance remained elevated and actually increased over the 12 to 16 hr post‐serum addition period (a time when early‐passage fibroblasts down‐regulate PAI‐1 mRNA content). Development of the senescent phenotype in human fibroblasts is associated, therefore, with significant changes in PAI‐1 gene regulation. Such reprogramming involves predominantly transcriptional events and results in a marked increase in steady‐state PAI‐1 transcript abundance involving both the 3.0‐ and 2.2‐kb mRNA species. J. Cell. Physiol. 174:90–98, 1998. © 1998 Wiley‐Liss, Inc.