Catalytic inhibitor of Protein Phosphatase 5 activates the extrinsic apoptotic pathway by disrupting complex II in kidney cancer.

Serine/threonine protein phosphatase-5 (PP5) is involved in tumor progression and survival, making it an attractive therapeutic target. Specific inhibition of protein phosphatases has remained challenging because of their conserved catalytic sites. PP5 contains its regulatory domains within a single polypeptide chain, making it a more desirable target. Here we used an in silico approach to screen and develop a selective inhibitor of PP5. Compound P053 is a competitive inhibitor of PP5 that binds to its catalytic domain and causes apoptosis in renal cancer. We further demonstrated that PP5 interacts with FADD, RIPK1, and caspase 8, components of the extrinsic apoptotic pathway complex II. Specifically, PP5 dephosphorylates and inactivates the death effector protein FADD, preserving complex II integrity and regulating extrinsic apoptosis. Our data suggests that PP5 promotes renal cancer survival by suppressing the extrinsic apoptotic pathway. Pharmacologic inhibition of PP5 activates this pathway, presenting a viable therapeutic strategy for renal cancer.

Gradient Expression of Transcription Factor Imposes a Boundary on Organ Regeneration Potential in Plants.

A wide variety of multicellular organisms across the kingdoms display remarkable ability to restore their tissues or organs when they suffer damage. However, the ability to repair damage is not uniformly distributed throughout body parts. Here, we unravel the elusive mechanistic basis of boundaries on organ regeneration potential using root tip resection as a model and show that the dosage of gradient-expressed PLT2 transcription factor is the underlying cause. While transient downregulation of PLT2 in distinct set of plt mutant backgrounds renders meristematic cells incapable of regeneration, forced expression of PLT2 acts through auto-activation to confer regeneration potential to the cells undergoing differentiation. Surprisingly, sustained exposure to nuclear PLT2, beyond a threshold, leads to reduction of regeneration potential despite giving rise to longer meristem. Our studies reveal dosage-dependent role of gradient-expressed PLT2 in root tip regeneration and uncouple the size of an organ from its regeneration potential.

De novo assembly of plant body plan: a step ahead of Deadpool.

While in the movie Deadpool it is possible for a human to recreate an arm from scratch, in reality plants can even surpass that. Not only can they regenerate lost parts, but also the whole plant body can be reborn from a few existing cells. Despite the decades old realization that plant cells possess the ability to regenerate a complete shoot and root system, it is only now that the underlying mechanisms are being unraveled. De novo plant regeneration involves the initiation of regenerative mass, acquisition of the pluripotent state, reconstitution of stem cells and assembly of regulatory interactions. Recent studies have furthered our understanding on the making of a complete plant system in the absence of embryonic positional cues. We review the recent studies probing the molecular mechanisms of de novo plant regeneration in response to external inductive cues and our current knowledge of direct reprogramming of root to shoot and vice versa. We further discuss how de novo regeneration can be exploited to meet the demands of green culture industries and to serve as a general model to address the fundamental questions of regeneration across the plant kingdom.