P16/INK4a controls the morphology program associated with cellular senescence

Background: Cellular senescence is a state which normal cells enter following an extensive period of proliferation or upon exposure to various kinds of stress. The senescence program involves G1 arrest accompanied by dramatic changes in cell function and morphology. The molecular mechanisms that govern these changes are at this point only partly understood. <br>Results: We here demonstrate that the p16 protein controls the morphological aspects of the senescence program. Inactivation of the p16 gene in senescent human cells causes the loss of the enlarged, flattened senescent phenotype, while growth arrest remains unaffected. Instead, cells attain a new phenotype with small, round cell morphology. In the course of this morphology change, p16 inactivation results in rearrangement of the actin cytoskeleton and the loss of the extensive web of actin stress-fibers typically present in senescent cells. <br>Young dividing cells with inactivated p16 do not attain the classical senescent phenotype if propagated in culture, while they do cease to divide. Doing so, they change their morphology to exhibit the same appearance as when disrupting p16 expression in senescent fibroblasts, again accompanied by rearrangements in actin cytoskeletal structure. <br>We find that p16 inactivation leads to a decrease in GTP-bound Rac levels and to an increase in GTP-bound Rho and Cdc42, while p16 overexpression has the opposite effect on the activity of these regulators of cytoskeletal structure. <br>Conclusions: Our findings indicate that the p16/INK4a gene product, a known inhibitor of cell cycle progression, also plays a key role in regulating the cytoskeletal program associated with cellular senescence.

Author dc:creator

• Voß, Martin Henner

Contributors dc:contributor

• Waller, Cornelius

• p16, Rb
• Seneszenz
• Lentivirus
• siRNA
• p16
• Rb
• senescence

Repository record source_url

https://freidok.uni-freiburg.de/data/2077

OAI identifier oai:identifier

oai:freidok.uni-freiburg.de:2077