Pim-1 kinase stimulates c-Myc-mediated death signaling upstream of caspase-3 (CPP32)-like protease activation

Abstract

Pim-1 oncoprotein is a serine/threonine kinase that can closely cooperate with c-Myc in lymphomagenesis, as does Bcl-2. Although the molecular mechanism of this cooperative transformation remains unknown, it is speculated that, similar to Bcl-2, Pim-1 contributes to transformation by inhibiting apoptosis. In this study, therefore, we examined the e ect of Pim-1 expression on c-Myc-mediated apoptosis of Rat-1 ®broblasts triggered by serum deprivation. Our results showed that, rather than inhibiting apoptosis, Pim-1 expression stimulated cMyc-mediated apoptosis in Rat-1 ®broblasts. Pim-1 stimulated c-Myc-mediated apoptosis through an enhancement of the c-Myc-mediated activation of caspase-3 (CPP32)-like proteases, since the suppression of this activity by a speci®c caspase inhibitor abolished the apoptosis stimulation by Pim-1. A kinase-defective Pim-1 mutant failed to stimulate c-Myc-mediated apoptosis, and Pim-1 expression alone in the absence of c-Myc overexpression did not induce apoptosis of serumdeprived Rat-1 cells, indicating that the kinase activity of Pim-1 and the activated c-Myc signaling pathway were required for apoptosis stimulation by Pim-1. Together, these results suggest that Pim-1 oncoprotein stimulates as a serine/threonine kinase the death signaling elicited by c-Myc at a step upstream of caspase-3-like protease activation in Rat-1 ®broblasts. Our results also suggest that Pim-1 kinase might function cooperatively with c-Myc through the phosphorylation of a factor(s) which regulates the common signaling pathway involved in c-Myc-mediated apoptosis and transformation.

Runx2: A novel oncogenic effector revealed by in vivo complementation and retroviral tagging

“…However, if Runx2 acts by abrogation of Myc-induced apoptosis, this would appear to be dependent on the in vivo context as we also found that Runx2 was unable to prevent apoptosis induced by a regulatable form of Myc (CD2-MYC-ER TM ) in lines established directly from tumours (Vaillant et al, 1999;Blyth et al, 2000). In a similar fashion, the critical oncogenic function of the Pim1 kinase has not been de®ned clearly but an antiapoptotic role has been noted in some studies (Lilly and Kraft, 1997;Leverson et al, 1998;Lilly et al, 1999;Shirogane et al, 1999) while others have suggested that Pim1 acts to amplify Myc signalling in a pro-apoptotic manner (Mochizuki et al, 1997(Mochizuki et al, , 1999.…”

Pim1 and Myc reversibly transform murine precursor B lymphocytes but not mature B lymphocytes

“…Expression of Pim1 is upregulated upon CD40 signaling in mature B cells [23]. Pim1 has been shown to enhance [24] or decrease [25] cell survival, depending on the cellular context. Furthermore, Pim1 is involved in the transition from G2 to M-phase during cell cycle [26].…”

Pim-1 kinase protects hematopoietic FDC cells from genotoxin-induced death

“…This included the inhibition of PCD-associated decays in mitochondrial membrane potential, and of the production of reactive oxygen species. By comparison, studies by Mochizuki et al (1997Mochizuki et al ( , 1999 of the e ects of the forced co-expression of Pim-1 with either Cdc25a or c-Myc in Rat-1 ®broblasts have yielded somewhat disparate results. In this model, Pim-1 increased rates of Cdc25a-dependent transformation to anchorage-independent growth but also at the same time somewhat increased rates of PCD beyond those induced by the over-expression of these additional oncogenic factors.…”