title: Mitogen-activated protein kinase p38 and retinoblastoma protein signalling is required for DNA damage-mediated formation of senescence-associated heterochromatic foci in tumour cells.
abstract: DNA-damaging agents are able to induce irreversible cell growth arrest and senescence in some types of tumour cells, thus contributing to the static feature of cancer. However, senescent tumour cells may re-enter the cell cycle, leading to tumour relapse. Understanding the mechanisms that control the viability of senescent cells may be critical for tumour suppression. Primary human fibroblasts undergoing oncogene-induced or replicative senescence are known to form senescence-associated heterochromatin foci (SAHF), which contribute to the stability of the senescent state. However, it is unclear whether SAHF formation is universal in tumour cells. We report that the DNA-damaging agents doxorubicin and 7-ethyl-10-hydroxycamptothecin were able to induce the formation of SAHF in some tumour cell types, and this induction was accompanied by activation of the retinoblastoma protein pathway. By contrast, tumour cells in which the retinoblastoma protein pathway could not be activated by doxorubicin or 7-ethyl-10-hydroxycamptothecin failed to form SAHF. In parallel, tumour cells with deficient retinoblastoma protein were also unable to form SAHF. In addition, we show that the mitogen-activated protein kinase p38 pathway was involved in tumour cell SAHF formation in response to doxorubicin and 7-ethyl-10-hydroxycamptothecin. Furthermore, HMG box transcription factor 1 (HBP1), a downstream target of the mitogen-activated protein kinase p38-mediated senescence pathway, was required for SAHF formation. Taken together, the results of the present study highlight the roles of the mitogen-activated protein kinase p38/retinoblastoma protein pathway in tumour cell SAHF formation in response to DNA-damaging agents, and provide new insights into the mechanisms of DNA damage-mediated tumour suppression.
authors.affiliation: The Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Gao
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.forename: Liping
authors.initials: L
authors.lastname: Han
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Pingfu
authors.initials: P
authors.lastname: Hou
authors.forename: Xi
authors.initials: X
authors.lastname: Shi
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Baoqing
authors.initials: B
authors.lastname: Tian
authors.forename: Xiuli
authors.initials: X
authors.lastname: Wang
authors.forename: Baiqu
authors.initials: B
authors.lastname: Huang
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006570:Heterochromatin / Q000187:drug effects / Q000235:genetics* / Q000473:pathology; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D009928:Organ Specificity; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C486328:HBP1 protein, human; D006570:Heterochromatin; D006609:High Mobility Group Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D000077146:Irinotecan; D004317:Doxorubicin; D048051:p38 Mitogen-Activated Protein Kinases; D002166:Camptothecin
keywords: HBP1; Rb; p38 MAPK; senescence-associated heterochromatin foci; tumour cells