LYL1 Degradation by the Proteasome Is Directed by a N-Terminal PEST Rich Site in a Phosphorylation-Independent Manner

Background: The Lymphoblastic leukemia 1 (LYL1) gene is a proto-oncogenic transcription factor found upregulated in patients with T-cell acute lymphoblastic leukemia (T-cell ALL). Initially, the upregulation was described to be as a result of a translocation. However, further studies revealed that transcriptional upregulation of LYL1could also occur without translocations. In addition, post-translational mechanisms, such as protein degradation could influence LYL1 expression as well. Methodology/Principal Findings: In this study, we considered possible post-translational regulation of Lyl1, and investigated fundamental mechanisms governing LYL1 degradation in cell-based culture assays. We identify a PEST sequence motif located in the N-terminus of LYL1, which determines the efficiency of LYL1 degradation by the proteasome. The absence of the PEST degradation site leads to accumulation or upregulation of LYL1. We also show that LYL1 is phosphorylated by MAPK at S36, and determined that proteasomal degradation of LYL1 occurs in a phosphorylationindependent manner. Conclusions/Significance: Understanding LYL1 degradation is a step forward not only towards deciphering the normal function and regulation of LYL1, but could suggest post-translational mechanisms for upregulation of LYL1 that ma

Ataxin1L is a regulator of HSC function highlighting the utility of cross-tissue comparisons for gene discovery.

Hematopoietic stem cells (HSCs) are rare quiescent cells that continuously replenish the cellular components of the peripheral blood. Observing that the ataxia-associated gene Ataxin-1-like (Atxn1L) was highly expressed in HSCs, we examined its role in HSC function through in vitro and in vivo assays. Mice lacking Atxn1L had greater numbers of HSCs that regenerated the blood more quickly than their wild-type counterparts. Molecular analyses indicated Atxn1L null HSCs had gene expression changes that regulate a program consistent with their higher level of proliferation, suggesting that Atxn1L is a novel regulator of HSC quiescence. To determine if additional brain-associated genes were candidates for hematologic regulation, we examined genes encoding proteins from autism- and ataxia-associated protein-protein interaction networks for their representation in hematopoietic cell populations. The interactomes were found to be highly enriched for proteins encoded by genes specifically expressed in HSCs relative to their differentiated progeny. Our data suggest a heretofore unappreciated similarity between regulatory modules in the brain and HSCs, offering a new strategy for novel gene discovery in both systems.open1112sciescopu

Novel molecular classifications of DLBCL

International audienc

Muscle stem cell dysfunction impairs muscle regeneration in a mouse model of Down syndrome

Abstract Down syndrome, caused by trisomy 21, is characterized by a variety of medical conditions including intellectual impairments, cardiovascular defects, blood cell disorders and pre-mature aging phenotypes. Several somatic stem cell populations are dysfunctional in Down syndrome and their deficiencies may contribute to multiple Down syndrome phenotypes. Down syndrome is associated with muscle weakness but skeletal muscle stem cells or satellite cells in Down syndrome have not been investigated. We find that a failure in satellite cell expansion impairs muscle regeneration in the Ts65Dn mouse model of Down syndrome. Ts65Dn satellite cells accumulate DNA damage and over express Usp16, a histone de-ubiquitinating enzyme that regulates the DNA damage response. Impairment of satellite cell function, which further declines as Ts65Dn mice age, underscores stem cell deficiencies as an important contributor to Down syndrome pathologies