Allen, W. L. | Search bioRxiv

bioRxiv2019

FLIP(L) determines p53 induced life or death

How p53 differentially activates cell cycle arrest versus cell death remains poorly understood. Here, we demonstrate that upregulation of canonical pro-apoptotic p53 target genes in colon cancer cells imposes a critical dependence on the long splice form of the caspase-8 regulator FLIP (FLIP(L)), which we identify as a direct p53 transcriptional target. Inhibiting FLIP(L) expression with siRNA or Class-I HDAC inhibitors promotes apoptosis in response to p53 activation by the MDM2 inhibitor Nutlin-3A, which otherwise predominantly induces cell-cycle arrest. When FLIP(L) upregulation is inhibited, apoptosis is induced in response to p53 activation via a novel ligand-independent TRAIL-R2/caspase-8 complex, which, by activating BID, induces mitochondrial-mediated apoptosis. Notably, FLIP(L) depletion inhibits p53-induced expression of the cell cycle regulator p21 and enhances p53-mediated upregulation of PUMA, with the latter activating mitochondrial-mediated apoptosis in FLIP(L)-depleted, Nutlin-3A-treated cells lacking TRAIL-R2/caspase-8. Thus, we report two previously undescribed, novel FLIP(L)-dependent mechanisms that determine cell fate following p53 activation.

cancer biology↗

bioRxiv2019

The structure of species discrimination signals across a primate radiation

Discriminating between conspecifics and heterospecifics potentially challenging for closely related sympatric species. The guenons, a recent primate radiation, exhibit high degrees of sympatry and form multi-species groups in which hybridization is possible but rare in most populations. Guenons have species-specific colorful face patterns hypothesized to function in species discrimination. Here, we apply a novel machine learning approach to identify the face regions most essential for correct species classification across fifteen guenon species. We then demonstrate the validity of these computational results using experiments with live guenons, showing that facial traits identified as critical for accurate classification do indeed influence selective attention toward con- and heterospecific faces. Our results suggest variability among guenon species in reliance on single-trait-based versus holistic facial characteristics when discriminating between species, and differences in behavioral responses to faces can be linked to whether discrimination is based on a single trait or whole-face pattern. Our study supports the hypothesis that guenon face patterns function to promote species discrimination and provides novel insights into the relationship between species interactions and phenotypic diversity.

evolutionary biology↗