p53 Mediates Apoptotic Crisis in Primary Abelson Virus-Transformed Pre-B Cells

Abstract

Transformation of pre-B cells by Abelson murine leukemia virus (Ab-MLV) involves a balance between positive, growth-stimulatory signals from the v-Abl oncoprotein and negative regulatory cues from cellular genes. This phenomenon is reflected by the clonal selection that occurs during Ab-MLV-mediated transformation in vivo and in vitro. About 50% of all Ab-MLV-transformed pre-B cells express mutant forms of p53 as they emerge from this process, suggesting that this protein may play an important role in the transformation process. Consistent with this idea, expression of p19(Arf), a protein whose function depends on the presence of a functional p53, is required for the apoptotic crisis that characterizes primary Ab-MLV transformants. To test the role of p53 in pre-B-cell transformation directly, we examined the response of Trp53(-/-) mice to Ab-MLV. The absence of p53 shortens the latency of Abelson disease induction but does not affect the frequency of cells susceptible to Ab-MLV-induced transformation. However, primary transformants derived from the null animals bypass the apoptotic crisis that characterizes the transition from primary transformant to fully malignant cell line. These effects do not require p21(Cip-1), a major downstream target of p53; however, consistent with a role of p19(Arf), transformants expressing mutant p53 and abundant p19 retain wild-type p19 sequences.

p53 Is Necessary for the Apoptotic Response Mediated by a Transient Increase of Ras Activity

“…In contrast, we find no evidence of a role for p53 in the regulation of apoptosis in cells that stably express v-ras. During the early stage of transformation, cells undergo a period of crisis in which the majority of cells die before permanent establishment of malignancy (21,43,49,51,53). This phenomenon has also been noticed in the establishment of immortal cell lines.…”

“…Tumor formation is a multistep process involving positive, growth-stimulatory signals which permit uncontrolled cell proliferation and negative, protective regulation that eliminates unlimited growth through the induction of an apoptotic crisis (21,43,49,51,53). These two conflicting signals often occur simultaneously during the transformation process, in which p53 has been implicated as a crucial regulator (3,28).…”

Inhibition of v-Abl transformation by p53 and p19ARF

“…mice can bypass apoptotic crisis and become established very rapidly, suggesting that p53 and p19ARF restrict transformation of pre-B cells by v-Abl (Radfar et al, 1998;Unnikrishnan et al, 1999). Disruption of p53 function facilitates v-Abl transformation not only in vitro, but also in vivo.…”

Transforming pathways activated by the v-Abl tyrosine kinase

“…The critical role for p53 in v-Ablinduced leukemia was confirmed by examining v-Abl transforming activity in p53-deficient or heterozygous mice. p53 null mice succumbed to A-MuLV induced leukemia with a rate almost twice that of either wild type or heterozygous animals (Unnikrishnan et al, 1999;Zou et al, 2000). A-MuLV-infected primary lymphoid cells from p53 null mice escaped p53-mediated apoptotic crisis, whereas wild type (p53 +/+ ) and heterozygous (p53 +/7 ) infected cells did not.…”