Induction of G1 checkpoint in the gastric mucosa of aged rats.

Although in Fischer 344 rats aging is found to be associated with increased gastric mucosal proliferative activity, little is known about specific changes in the regulatory mechanisms of this process. To determine whether changes in cell cycling events could partly contribute to the age-related rise in gastric mucosal proliferative activity, the present investigation examines changes in cyclin-dependent kinase (Cdk2) activity and the regulation of this process in the gastric mucosa of Fischer 344 rats aged 4 (young), 13 (middle aged), and 24 (old) mo. We observed that aging is associated with a progressive rise in activity and protein levels of Cdk2 in the gastric mucosa. This is also found to be accompanied by a concomitant increase in cyclin E but not cyclin D1 levels. On the other hand, the levels of p21Waf1/Cip1 (total as well as the fraction associated with Cdk2), a nuclear protein that is known to inhibit different cyclin-Cdk complexes, are found to decline in the gastric mucosa with advancing age. In contrast, with aging, there was a steady rise in p53 levels in the gastric mucosa. We have also observed that the levels of phosphorylated retinoblastoma protein, a form that participates in regulating progression through the S phase, are markedly elevated in the gastric mucosa of aged rats. In conclusion, our data suggest that, in the gastric mucosa, aging enhances transition of G1 to S phase as well as progression through the S phase of the cell cycle. However, the age-related decline in p21Waf1/Cip1 in the gastric mucosa appears to be independent of p53 status.

[1]  S. Winawer,et al.  Cell proliferation kinetics in the gastrointestinal tract of man. IV. Cell renewal in the intestinalized gastric mucosa. , 1969, Journal of the National Cancer Institute.

[2]  M. Montenarh,et al.  p21WAF1/CIP1 interacts with protein kinase CK2. , 1996, Oncogene.

[3]  S. Fligiel,et al.  Aging diminishes gastric mucosal regeneration: relationship to tyrosine kinases. , 1994, Laboratory investigation; a journal of technical methods and pathology.

[4]  J. Goldenring,et al.  Localization and significance of pp55, a gastric mucosal membrane protein with tyrosine kinase activity. , 1998, American journal of physiology. Gastrointestinal and liver physiology.

[5]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[6]  David O. Morgan,et al.  Principles of CDK regulation , 1995, Nature.

[7]  C. Sherr,et al.  D-type cyclins. , 1995, Trends in biochemical sciences.

[8]  John Kuriyan,et al.  Structure of the C-Terminal Region of p21WAF1/CIP1 Complexed with Human PCNA , 1996, Cell.

[9]  S. Elledge,et al.  The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases , 1993, Cell.

[10]  P. Holt,et al.  Gastrointestinal proliferation and aging. , 1993, Journal of gerontology.

[11]  A. Majumdar,et al.  The aging gastrointestinal tract, liver, and pancreas. , 1985, Clinics in geriatric medicine.

[12]  G. Hannon,et al.  The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA , 1994, Nature.

[13]  M. Nakanishi,et al.  The C-terminal Region of p21 Is Involved in Proliferating Cell Nuclear Antigen Binding but Does Not Appear to Be Required for Growth Inhibition (*) , 1995, The Journal of Biological Chemistry.

[14]  D. Kotler,et al.  Altered controls of proliferation in proximal small intestine of the senescent rat. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[15]  E. Edgerton,et al.  Gastrin: levels and trophic action during advancing age. , 1988, The American journal of physiology.

[16]  James M. Roberts,et al.  Inhibitors of mammalian G1 cyclin-dependent kinases. , 1995, Genes & development.

[17]  J. R. Smith,et al.  Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. , 1994, Experimental cell research.

[18]  B. Creamer,et al.  The turnover and shedding of epithelial cells , 1961, Gut.

[19]  B. Evers,et al.  Cell cycle protein suppression and p21 induction in differentiating Caco-2 cells. , 1996, The American journal of physiology.

[20]  E. Nigg,et al.  Cyclin‐dependent protein kinases: Key regulators of the eukaryotic cell cycle , 1995, BioEssays : news and reviews in molecular, cellular and developmental biology.

[21]  L. Johnson,et al.  Gastric mucosal cell proliferation during development in rats and effects of pentagastrin. , 1982, The American journal of physiology.

[22]  E. Edgerton,et al.  Gastric mucosal tyrosine kinase activity during aging and its relationship to cell proliferation in rats. , 1988, Biochimica et biophysica acta.

[23]  E. Harlow,et al.  Antibodies specific for the human retinoblastoma protein identify a family of related polypeptides , 1991, Molecular and cellular biology.

[24]  S. Winawer,et al.  Patterns of nucleic acid and protein synthesis in normal human gastric mucosa and atrophic gastritis. , 1972, Journal of the National Cancer Institute.

[25]  J. Tureaud,et al.  Role of tyrosine kinases in bombesin regulation of gastric mucosal proliferative activity in young and aged rats , 1992, Peptides.

[26]  J. Little,et al.  Potential Role of WAF1/Cip1/p21 as a Mediator of TGF-β Cytoinhibitory Effect (*) , 1995, The Journal of Biological Chemistry.

[27]  A. Gartel,et al.  p21—Negative Regulator of the Cell Cycle , 1996, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[28]  R. Weinberg,et al.  Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. , 1994, Genes & development.

[29]  C. P. Leblond,et al.  Renewal of chief cells and goblet cells in the small intestine as shown by radioautography after injection of thymidine‐H3 into mice , 1958, The Anatomical record.

[30]  S. van den Heuvel,et al.  Distinct roles for cyclin-dependent kinases in cell cycle control. , 1993, Science.

[31]  S. Elledge,et al.  Inhibition of cyclin-dependent kinases by p21. , 1995, Molecular biology of the cell.

[32]  A. Majumdar,et al.  Aging: altered responsiveness of gastric mucosa to epidermal growth factor. , 1989, The American journal of physiology.

[33]  P. Holt,et al.  Colonic proliferation is increased in senescent rats. , 1988, Gastroenterology.

[34]  E. A. Thompson,et al.  Intestinal cell cycle regulation. , 1997, Progress in cell cycle research.

[35]  A. Pardee,et al.  Cyclin E and cyclin A as candidates for the restriction point protein. , 1993, Cancer research.

[36]  T. Ide,et al.  Increase in expression level of p21sdi1/cip1/waf1 with increasing division age in both normal and SV40-transformed human fibroblasts. , 1995, Oncogene.

[37]  M. Dubick,et al.  Effect of Aging on the Gastrointestinal Tract and the Pancreas , 1997, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.