Transcriptional control of cell cycle-dependent kinase 4 by Smad proteins—implications for Alzheimer's disease

Pin1 promotes degradation of Smad proteins and their interaction with phosphorylated tau in Alzheimer's disease

“…Altogether, this provides evidence for a negative feed‐back regulation of Pin1 by Smad. A similar mechanism might be instrumental in AD, where nuclear Smad concentrations are significantly reduced [12], which potentially contributes to increased levels of Pin1 [16].…”

“…( A ) PIN1 promoter region with potential Smad binding elements ( SBE ). Potential SBE ‐sequences ( GTCT , AGAC , AGGC ; GCCT ) are highlighted in grey (for more information see [12]). Sequences of probes P 1 to P 4 which are used for EMSA studies are labelled by boxes.…”

“…Smad proteins play an important role in neuronal development, differentiation and cellular homeostasis. The reduction of soluble neuronal Smad content is a characteristic feature of several neurodegenerative disorders including AD [9,10,13] where it might contribute to the dysregulated expression of a variety of disease‐associated genes including those controlling the cell cycle [12]. Here, we could show that Smad proteins are localized within cytoplasmic granules a pathological deposition containing both Pin1 and tau [15].…”

The Role of Smad Proteins for Development, Differentiation and Dedifferentiation of Neurons

“…Additionally a significant reduction of Smad2,3,4, which are involved in activation of cell cycle proteins was described. Smad4 directly controls cyclin-dependent kinase 4 (CDK4) expression in neuronal cells and is involved in cell cycle activation of neurons in AD brain [192]. It is quite possible, that the recently identified TGFβ1-induced antiapoptotic factor (TIAF1), which can bind and block Smad4-dependent promoter activation [193], participates in the cytoplasmic Smad sequestration in AD neurons and suppresses Smad-regulated promoter activation.…”

Advances with RNA interference in Alzheimer’s disease research

“…In the normal adult brain, Smad proteins are constitutively phosphorylated and predominantly localized in neuronal nuclei 74. Using RNAi in cell cultures to mimic the neuronal deficiency of Smad proteins observed in AD results in elevation of cell cycle-dependent kinase 4 and retardation of neurite outgrowth, giving rise to neuronal dedifferentiation and cell death 75. Polo-like kinase 1 (Plk1) is an established regulator of many cell cycle-related events.…”