The cytostatic function of c-Abl is controlled by multiple nuclear localization signals and requires the p53 and Rb tumor suppressor gene products.
c-Abl is a non-receptor protein-tyrosine kinase lacking a clear physiological role. A clue to its normal function is suggested by overexpression of Abl in fibroblasts, which leads to inhibition of cell growth. This effect requires tyrosine kinase activity and the Abl C-terminus. c-Abl is localized to the cell nucleus, where it can bind DNA, and interacts with the retinoblastoma protein, a potential mediator of the growth-inhibitory effect. Nuclear localization of Abl can be directed by a pentalysine nuclear localization signal in the Abl C-terminus. Here, we have identified two additional basic motifs in the Abl C-terminus, either of which can function independently of the pentalysine signal to localize Abl to the nucleus. Using a quantitative transfection assay, we show that both c-Abl and transforming Abl proteins inhibit entry into S phase and this effect is absolutely dependent on nuclear localization. Further, we demonstrate that the Abl cytostatic effect requires both the Rb and p53 tumor suppressor gene products. These results indicate that Abl inhibits cell proliferation by interacting with central elements of the cell cycle control apparatus in the nucleus, and suggest a direct connection between p53 and Rb in this growth-inhibitory pathway.
Wen
S T
ST
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Jackson
P K
PK
Van Etten
R A
RA
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D016588:Anticarcinogenic Agents / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D017124:Conserved Sequence; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D016588:Anticarcinogenic Agents; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D016315:Proto-Oncogene Proteins c-abl