Implications of cellular senescence in tissue damage response, tumor suppression, and stem cell biology.
Cellular senescence is characterized by an irreversible cell cycle arrest that, when bypassed by mutation, contributes to cellular immortalization. Activated oncogenes induce a hyperproliferative response, which might be one of the senescence cues. We have found that expression of such an oncogene, Akt, causes senescence in primary mouse hepatoblasts in vitro. Additionally, AKT-driven tumors undergo senescence in vivo following p53 reactivation and show signs of differentiation. In another in vivo system, i.e., liver fibrosis, hyperproliferative signaling through AKT might be a driving force of the senescence in activated hepatic stellate cells. Senescent cells up-regulate and secrete molecules that, on the one hand, can reinforce the arrest and, on the other hand, can signal to an innate immune system to clear the senescent cells. The mechanisms governing senescence and immortalization are overlapping with those regulating self-renewal and differentiation. These respective control mechanisms, or their disregulation, are involved in multiple pathological conditions including fibrosis, wound healing, and cancer. Understanding extracellular cues that regulate these processes may enable new therapies for these conditions.
Krizhanovsky
V
V
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Xue
W
W
Zender
L
L
Yon
M
M
Hernando
E
E
Lowe
S W
SW
D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D016158:Genes, p53; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014945:Wound Healing
D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt