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Changes in corticotrope gene expression upon increased expression of peptidylglycine a-amidating monooxygenase, an evolutionarily conserved enzyme

ABSTRACT: Throughout evolution, secretion has played an essential role in the ability of organisms and single cells to survive in the face of a changing environment. PAM (peptidylglycine a-amidating monooxygenase) is an integral membrane monooxygenase first identified for its role in the biosynthesis of neuroendocrine peptides released by the regulated secretory pathway. By screening for transcripts whose expression in a corticotrope tumor cell line responded to changes in PAM levels, we sought to identify genes not previously known to play a role in secretion. We identified transcription factors, peptidyl prolyl isomerases, endosomal/lysosomal proteins and proteins involved in tissue-specific responses to glucose and amino acid availability that had not previously been recognized as participants in secretion.

ORGANISM(S): Mus musculus

PROVIDER: GSE110809 | GEO | 2018/05/01

REPOSITORIES: GEO

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Project description:The molecular chaperons FK506-binding proteins (Fkbps) comprise one of three families of peptidyl prolyl isomerases, which promote the transition between cis- and trans-conformations of peptidyl prolyl bonds. Mouse Fkbp family is composed of at least 15 members, but the functions of the large family in cell proliferation and differentiation remain elusive. During myoblast differentiation, the cells need to exit the cell cycle before fusion and terminal differentiation to form myotubes. The clear distinction between proliferation and differentiation provides an ideal model with which to investigate the roles of Fkbps in these two cell biological events. We found that depletion of FkbpC in mouse myoblasts delayed the exit from the cell cycle and expression of myotube-specific genes, whereas its overexpression caused opposite effects. At a mechanistic level, our study revealed a crucial function of FkbpC in Cdk4 activation during myoblast proliferation. Cdk4 undergoes conformational changes in the HSP90/Cdc37/Cdk4 complex as a prerequisite for activation through binding to CyclinD1 accompanied by phosphorylation. Our results showed that FkbpC depletion released Cdk4 from the HSP90 complex, which increased the Cdk4/CyclinD1 complex in myoblasts and sustained high levels of phosphorylated Cdk4 and Rb during differentiation. These results explain the delayed cell cycle exit and differentiation in the depleted cells. In addition, after synchronizing the cell cycle of myoblasts we found dynamic changes of the amounts of FkbpC and Cdk4 in the HSP90 complex during the G1/S transition. Knockout mice of FkbpC demonstrated delayed muscle regeneration after chemical damage, providing an in vivo evidence for the essential role of FkbpC in muscle differentiation. Collectively, our study uncovered FkbpC's critical function as a novel switch regulating the transition from proliferation to differentiation through controlling one of the central regulators of proliferation, Cdk4.

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Changes in corticotrope gene expression upon increased expression of peptidylglycine a-amidating monooxygenase, an evolutionarily conserved enzyme

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