p21 delays tumor onset by preservation of chromosomal stability.
The p53 protein suppresses tumorigenesis by initiating cellular functions such as cell cycle arrest and apoptosis in response to DNA damage. A p53 mutant, p53R172P, which is deficient for apoptosis but retains a partial cell cycle arrest function, delays tumor onset in mice. Remarkably, lymphomas arising in Trp53(515C/515C) mice (encoding p53R172P) retain stable genomes. Given the dominant role of p21 in p53 cell cycle control, we crossed Trp53(515C/515C) mice onto a p21-null background to determine whether p21 was required for maintaining chromosomal stability and delaying tumor onset. Loss of p21 completely abolished the cell cycle arrest function of p53R172P and accelerated tumor onset in Trp53(515C/515C) mice. Cytogenetic examination of Trp53(515C/515C) p21(-/-) sarcomas and lymphomas revealed aneuploidy and chromosomal aberrations that were absent in Trp53(515C/515C) malignancies. Thus, p21 coupled p53-dependent checkpoint control and preservation of chromosomal stability, and cooperated with apoptosis in suppressing tumor onset in mice.
Barboza
Juan A
JA
Department of Cancer Genetics and Pathology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Liu
Geng
G
Ju
Zhenlin
Z
El-Naggar
Adel K
AK
Lozano
Guillermina
G
D000818:Animals; D017209:Apoptosis; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins