Active Akt and functional p53 modulate apoptosis in Abelson virus-transformed pre-B cells.
Suppression of apoptosis is an important feature of the Abelson murine leukemia virus (Ab-MLV) transformation process. During multistep transformation, Ab-MLV-infected pre-B cells undergo p53-dependent apoptosis during the crisis phase of transformation. Even once cells are fully transformed, an active v-Abl protein tyrosine kinase is required to suppress apoptosis because cells transformed by temperature-sensitive (ts) kinase mutants undergo rapid apoptosis after a shift to the nonpermissive temperature. However, inactivation of the v-Abl protein by a temperature shift interrupts signals transmitted via multiple pathways, making it difficult to identify those that are critically important for the suppression of apoptosis. To begin to dissect these pathways, we tested the ability of an SH2 domain Ab-MLV mutant, P120/R273K, to rescue aspects of the ts phenotype of pre-B cells transformed by the conditional kinase domain mutant. The P120/R273K mutant suppressed apoptosis at the nonpermissive temperature, a phenotype correlated with its ability to activate Akt. Apoptosis also was suppressed at the nonpermissive temperature by constitutively active Akt and in p53-null pre-B cells transformed with the ts kinase domain mutant. These data indicate that an intact Src homology 2 (SH2) domain is not critical for apoptosis suppression and suggest that signals transmitted through Akt and p53 play an important role in the response.
Gong
Li
L
Department of Molecular Biology and Microbiology, School of Medicine, Tufts University, Boston, Massachusetts 02111, USA.
Unnikrishnan
Indira
I
Raghavan
Anuradha
A
Parmar
Kalindi
K
Rosenberg
Naomi
N
D000011:Abelson murine leukemia virus / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000821:virology*; D001854:Bone Marrow Cells / Q000821:virology*; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D006801:Humans; D051379:Mice; D016374:Oncogene Proteins v-abl / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains
D016374:Oncogene Proteins v-abl; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt