Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival

Abstract

Prostate apoptosis response protein 4 (Par-4) also known as PRKC apoptosis WT1 regulator is a tumor suppressor that selectively induces apoptosis in cancer cells. However, its post-translational regulation by ubiquitin-mediated proteolysis and the cellular machinery that is responsible for its proteasomal degradation are unknown. Using immunopurification and an unbiased mass spectrometry-based approach, we show that Par-4 interacts with the SPRY-domain containing E3 ubiquitin ligase Fbxo45 through a short consensus sequence motif. Fbxo45 interacts with Par-4 in the cytoplasm and mediates its ubiquitylation and proteasomal degradation. Fbxo45 silencing results in stabilization of Par-4 with increased apoptosis. Importantly, a Par-4 mutant that is unable to bind Fbxo45 is stabilized and further enhances staurosporine-induced apoptosis. Co-expression of Fbxo45 with Par-4 protects cancer cells against Par-4-induced apoptosis. Our studies reveal that Fbxo45 is the substratereceptor subunit of a functional E3 ligase for Par-4 that has a critical role in cancer cell survival.

PAM forms an atypical SCF ubiquitin ligase complex that ubiquitinates and degrades NMNAT2

“…In mature neurons, PHR proteins take on an important role in axon degeneration following injury (27,28). Outside of the nervous system, PHR proteins are implicated in oncogenesis (29)(30)(31)(32)(33)(34). Despite growing recognition of the functional importance of PHR proteins, relatively little is known about how components of atypical PHR ubiquitin ligase complexes assemble.…”

Fbxo45 joins the ‘Par-4’ty in controlling apoptosis of cancer cells

“…To address this critical question, this group detected the sensitivity of cancer cells expressing the Par-4 wild-type (WT) or Par-4 (3A) mutant to staurosporine-induced apoptosis. 15 To this end, they reported that cells expressing Par-4 (3A) mutant have a significant increase in the number of apoptotic cells compared to the cells with Par-4 (WT). 15 Consistently, TUNEL and western blot analyses for cleaved PARP-1 as additional apoptotic markers confirmed that Par-4 (3A) mutant promoted staurosporineinduced apoptosis.…”

“…15 To this end, they reported that cells expressing Par-4 (3A) mutant have a significant increase in the number of apoptotic cells compared to the cells with Par-4 (WT). 15 Consistently, TUNEL and western blot analyses for cleaved PARP-1 as additional apoptotic markers confirmed that Par-4 (3A) mutant promoted staurosporineinduced apoptosis. In support of this conclusion, they further showed that misregulated degradation of Par-4 by depletion of Fbxo45 or mutating the degron could also trigger cellular apoptosis.…”

“…In support of this conclusion, they further showed that misregulated degradation of Par-4 by depletion of Fbxo45 or mutating the degron could also trigger cellular apoptosis. 15 Although this interesting study shed important lights on the roles of Fbxo45 in regulation of apoptosis in cancer cells, a couple of critical questions still need to be answered in followup studies. For example, to validate the physiological role of Fbxo45 in vivo, Fbxo45 transgenic mice should be generated to address whether Fbxo45 facilitates tumorigenesis in part through Par-4 degradation.…”

“…In this issue of CDD, Chen et al 15 seek to understand the critical role and molecular mechanisms underlying Fbxo45-mediated ubiquitination of the Par-4 (prostate apoptosis response protein 4) tumor suppressor to regulate cancer cell survival (Figure 1). It has been well accepted that Par-4 functions as a tumor suppressor largely through induction of cellular apoptosis of cancer cells.…”