Down-Regulation of Ubiquitin Ligase Cbl Induced by Twist Haploinsufficiency in Saethre-Chotzen Syndrome Results in Increased PI3K/Akt Signaling and Osteoblast Proliferation

Abstract

Genetic mutations of Twist, a basic helix-loop-helix transcription factor, induce premature fusion of cranial sutures in Saethre-Chotzen syndrome (SCS). We report here a previously undescribed mechanism involved in the altered osteoblastogenesis in SCS. Cranial osteoblasts from an SCS patient with a Twist mutation causing basic helix-loop-helix deletion exhibited decreased expression of E3 ubiquitin ligase Cbl compared with wild-type osteoblasts. This was associated with decreased ubiquitin-mediated degradation of phosphatidyl inositol 3 kinase (PI3K) and increased PI3K expression and PI3K/Akt signaling.

E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

“…It is well known that the inhibition of PI3K/Akt activation by Cbl-b is dependent on a functional Cbl RING finger (18)(19)(20)(21)(22). Based on our research, this mutation could be responsible for the deregulation of proliferation of AML blasts and the promotion of resistance to ATO or chemotherapeutic agents.…”

“…The E3 ubiquitin ligase Cbl-b functions as a negative regulator of PI3K activation. Ubiquitination of the p85-regulatory subunit of PI3K by Cbl-b affects its phosphorylation of downstream substrates, including Akt (18)(19)(20)(21)(22). T lymphocytes from Cbl-b-deficient mice show enhanced proliferation and cytokine production in response to the triggering of T-cell receptors (22,23).…”

“…The combination of small molecule inhibitors of the PI3K/Akt pathway and standard chemotherapy has been successful in attenuating chemotherapeutic resistance, but further study of the molecules modulating PI3K/ Akt signaling is necessary. E3 ubiquitin ligase Cbl-b, a negative regulator of PI3K activation, is involved in several functions of T lymphocytes and osteoblasts (18)(19)(20)(21)(22). Cbl-b-deficient T lymphocytes show enhanced proliferation (22)(23)(24).…”

PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage

“…PKB in turn might behave as a functional mediator of Twist-1 and is involved in Twist-mediated chemotherapeutic drug resistance (Cheng et al, 2007;Zhang et al, 2007). Interestingly, Saethre-Chotzen syndrome resulting from Twist-1 haploinsufficiency displays decreased expression of Cbl ubiquitin ligase, resulting in the accumulation of phosphatidylinositol-3-kinase (PI3K) and increased PI3K/PKB signaling (Guenou et al, 2006).…”

Rôle de l’ubiquitine ligase c-Cbl dans l’ostéogenèse normale et cancéreuse

“…Les travaux de notre laboratoire ont cependant montré que c-Cbl régule la formation osseuse en contrôlant la dégradation de plusieurs protéines impliquées dans l'ostéoblastogenèse ( Figure 2B). Ainsi, la diminution de l'expression de c-Cbl induite par une mutation génétique du gène Twist provoque une augmentation de l'activité des voies de signalisations PI3K et Akt (protéine kinase B), ce qui entraîne une augmentation de la prolifé-ration des ostéoblastes [17]. En revanche, le recrutement de c-Cbl induit par l'activation du FGFR2 entraîne une diminution de l'expression des protéines Src, Lyn et Fyn, et d'autres récepteurs à activité tyrosine kinase, ce qui a pour effet d'augmenter l'expression des gènes ostéoblastiques En contrôlant l'ubiquitination et la dégradation d'un grand nombre de protéines, le système ubiquitine-protéasome est impliqué dans la régulation de processus cellulaires essentiels au développement de l'organisme (prolifération, différenciation, survie, etc.).…”