Twist1: A Double-Edged Sword in Kidney Diseases

Abstract

Background: Twist1 is a basic helix-loop-helix domain containing transcription factor that regulates cell differentiation, migration, proliferation, survival, and inflammatory responses by transcriptionally regulating a wide range of downstream target genes. Its homologous protein, Twist2, shares many structural and functional similarities with Twist1. Summary: Accumulating evidence from both preclinical and clinical studies suggests that Twist1 is a pivotal regulator of several forms of renal disease. Twist1 is persistently activated following renal insults, particularly in chronic kidney diseases, and contributes to the renal inflammatory responses, tubular cell transformation programs, and possibly fibroblast activation, all of which are involved in the initiation and progression of kidney diseases. Key Message: This review will specifically focus on Twist1 and outline our understanding of its functions in kidney disorders along with the introduction of Twist2 where pertinent. The thorough knowledge of Twist1’s actions in the pathogenesis of kidney diseases should facilitate the development of novel therapeutics for kidney injury.

TGFβ instructs mTORC2 to activate PKCβII for increased TWIST1 expression in proximal tubular epithelial cell injury

“…TWIST1 is undetectable in normal human kidney; however, it is significantly upregulated in patients with CKD [50]. Similarly, in adult mouse kidney, the level of TWIST1 is very low; however, expression of TWIST1 in the tubular epithelium is dramatically increased in many mouse models of renal fibrosis [28,51]. Deletion of TWIST1 in proximal tubular epithelial cells was protective in multiple experimental models of renal fibrosis involving TGFb [19].…”

Epithelial–Mesenchymal Transition by Synergy between Transforming Growth Factor-β and Growth Factors in Cancer Progression

“…Phosphorylation of TWIST1 regulates its transcriptional activity and protein stability. PKA phosphorylates Thr125 and Ser127 of TWIST1, and then enhances its dimerization and DNA binding through its bHLH domain [ 21 ]. Although Ser68 phosphorylation by ERK increases the stability of TWIST1, the small C-terminal domain phosphatase 1 (SCP1) dephosphorylates Ser68 and promotes degradation [ 22 , 23 ].…”

The Post-Translational Regulation of Epithelial–Mesenchymal Transition-Inducing Transcription Factors in Cancer Metastasis

“…Phosphorylation regulates the activity and stability of Twist1. Phosphorylation at Thr125 and Ser127 by PKA enhances Twist1 dimerization and DNA binding [ 148 ]. These phosphorylation sites are suppressed by protein phosphatase 2 [ 148 ].…”

“…Phosphorylation at Thr125 and Ser127 by PKA enhances Twist1 dimerization and DNA binding [ 148 ]. These phosphorylation sites are suppressed by protein phosphatase 2 [ 148 ]. Phosphorylation at Ser68 of Twist1 by MAPK has been reported to increase Twist1 stability in breast cancer cells [ 133 ].…”