title: Wild-type p16INK4a suppresses cell growth, telomerase activity and DNA repair in human breast cancer MCF-7 cells.
abstract: p16INK4a, a cell cycle inhibitor that inhibits cyclin-dependent kinase 4 (cdk4) and cdk6, has been found as the tumor suppressor gene and is frequently deleted, methylated or mutated in many malignancies. Since p16INK4a is also a key element controlling cellular senescence and other functions, we hypothesized that p16INK4a induced tumor suppression may not be limited to the inhibition of cdks. To investigate the role of p16INK4a in tumor suppression and the potential interaction between p16INK4a and other cellular controlling elements, such as telomerase activity and DNA repair ability, the full-length of p16INK4a cDNA was cloned into a retroviral vector and introduced into human breast cancer MCF-7 cells that were previously demonstrated to harbor homozygous deletions of the p16INK4a gene. Stable expression of p16INK4a suppressed the malignant phenotype in MCF-7 cells, including cell proliferation, anchorage-independent growth, G1/G0 cell cycle arrest, and the blockage of pRB phosphorylation. In addition, expression of p16INK4a suppressed telomerase activity and restored the telomere shortening process, and decreased cell DNA repair ability and sensitized cells to the DNA damage reagent. Our data suggest that the wild-type p16INK4a plays an important role in suppression of tumor malignancy, not only by inhibiting cell proliferation through cell cycle arrest, but also by inhibiting other cellular controlling mechanisms, such as telomerase activity and DNA repair capacity.
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100083, P.R. China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Duan
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: Pinghu
authors.initials: P
authors.lastname: Liu
authors.forename: Zongyu
authors.initials: Z
authors.lastname: Zhang
authors.forename: Tanjun
authors.initials: T
authors.lastname: Tong
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000368:Aged; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins; D005260:Female; D017353:Gene Deletion; D005822:Genetic Vectors; D006720:Homozygote; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D016160:Retinoblastoma Protein; D019098:Telomerase