Pim-1 regulates cardiomyocyte survival downstream of Akt

Abstract

The serine-threonine kinases Pim-1 and Akt regulate cellular proliferation and survival. Although Akt is known to be a crucial signaling protein in the myocardium, the role of Pim-1 has been overlooked. Pim-1 expression in the myocardium of mice decreased during postnatal development, re-emerged after acute pathological injury in mice and was increased in failing hearts of both mice and humans. Cardioprotective stimuli associated with Akt activation induced Pim-1 expression, but compensatory increases in Akt abundance and phosphorylation after pathological injury by infarction or pressure overload did not protect the myocardium in Pim-1-deficient mice. Transgenic expression of Pim-1 in the myocardium protected mice from infarction injury, and Pim-1 expression inhibited cardiomyocyte apoptosis with concomitant increases in Bcl-2 and Bcl-X(L) protein levels, as well as in Bad phosphorylation levels. Relative to nontransgenic controls, calcium dynamics were significantly enhanced in Pim-1-overexpressing transgenic hearts, associated with increased expression of SERCA2a, and were depressed in Pim-1-deficient hearts. Collectively, these data suggest that Pim-1 is a crucial facet of cardioprotection downstream of Akt.

Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells

“…For example, a recent study suggested that Pim and AKT work in concert to regulate survival and proliferation of nontransformed hematopoietic cells (Hammerman et al, 2005). More recently, another group described a novel discovery that Pim-1 is a crucial facet of cardioprotection downstream of AKT and that a feedback mechanism exists involving the two proteins (Muraski et al, 2007). Importantly, Pim kinases show similar substrate specificity as AKT.…”

“…Recent studies have revealed that AKT and Pim-1 show feedback relationship in some cell types (Muraski et al, 2007). It has also been found that AKT shows similar substrate specificity as Pim kinases.…”

“…Because induction of Pim-1 expression has recently been linked to AKT activation (Muraski et al, 2007), we explored whether AKT1(E17K) can regulate levels of Pim proteins in v-Abl transformants. To this end, we used v-Abl-transformed wild-type cells ectopically expressing AKT1(WT), AKT1(E17K) or GFP.…”

“…Moreover, we determined the possible role AKT1(E17K) mutation has in Abl transformation. Interestingly, recent studies have showed that the kinases AKT and Pim exhibit feedback relationship in several cell types (Hammerman et al, 2005;Muraski et al, 2007). Like AKT, Pim-1, Pim-2 and Pim-3 are serine/threonine kinases that constitute a distinct family involved in cell proliferation and survival.…”

Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

“…The serine/threonine kinase Pim-1 is a critical downstream effector of Akt-mediated cardioprotective signaling (15)(16)(17)(18). Pim-1 is antiapoptotic and proproliferative, and recent findings indicate that it also exerts beneficial effects in part by preserving mitochondrial integrity (15).…”