Stk11

Enchondroma resulting from loss of a Stk11-dependent switch of proliferative chondrocytes to a postmitotic fate

"Stk11 (also known as liver kinase b1 (Lkb1)) is a serine-threonine protein kinase that acts upstream of the AMP-activated protein kinase (AMPK) family in coupling energy homeostasis to cell growth, proliferation and survival. Through chondrocyte-specific removal of Lkb1 activity, we showed that Stk11 is required for the normal switch of mitotic chondrocytes to a postmitotic hypertrophic chondrocyte fate. Consequently, it led to a dramatic overgrowth of the growth plate in the Stk11-mutant postnatal skeletal elements. To determine the molecular mechanisms underlying Stk11 action, we examined the mTOR pathway, which is inhibited through AMPK in growth regulation. Strikingly, rapamycin treatment of the pregnant mouse was able to rescue the delay in chondrocyte hypertrophy in Stk11-mutant embryos, suggesting that Stk11 inhibition of mTOR signaling is critical for the switch in chondrocyte fate. Since the dramatic overgrowth of the growth plate is characteristic of enchondroma, we also examined the tumorigenicity of the mutant chondrocytes both in vitro and in vivo. In contrast to wild-type chondrocytes isolated from the postnatal day-30 growth plate, Stk11-mutant chondrocytes proliferated and formed colonies in monolayer and anchorage-independent agar cultures, indicative of a neoplastic transformation in vitro. Similarly, allotransplantation of mutant chondrocytes into immune-deficient NOG mice also resulted in tumor formation in vivo. Gene Ontology analysis of gene expression profiles indicated an augmented activity of cell proliferation and cell cycle regulators within the enchondroma-chondrocyte population compared to chondrocytes in the normal growth plate."

Loss of Stk11 (Lkb1) in Chondrocytes Delays Chondrocyte Hypertrophy Resulting in a Chondrosarcoma-like Overgrowth in the Postnatal Skeleton

"Stk11 is required for the normal switch of mitotic chondrocytes to a post-mitotic hypertrophic chondrocyte fate. We examined the mTOR pathway, which is inhibited by AMPK in growth regulation. Strikingly, rapamycin treatment of the pregnant mouse was able to rescue the delay in chondrocyte hypertrophy in Stk11 mutant embryos, suggesting that Stk11 inhibition of mTOR signaling is critical for the switch in chondrocyte fate. To determine the consequences of Stk11 removal in the postnatal skeleton, we examined long bones following chondrocyte specific removal of Stk11 at embryonic stages. Removal of Stk11 led to chondrosarcoma-like overgrowth phenotype in the Stk11 mutant skeletal elements. Furthermore, in contrast to wild-type chondrocytes isolated from the postnatal day 30 growth plate, Stk11 mutant chondrocytes proliferated and formed colonies in monolayer and anchorage-independent agar cultures, indicative of a neoplastic transformation. Gene Ontology analysis of gene expression profiles indicated an augmented activity of cell proliferation and cell cycle regulators within the chondrosarcoma-like population compared to chondrocytes in the normal growth plate. Stk11 [balances] proliferative and non-proliferative hypertrophic states of chondrocyte development through the regulation of mTOR signaling."