Biomedical subjects

Baldwin C Mak

Publications and source records attributed to Baldwin C Mak.

4 recordsLinked to original sources

PubMed2005

Aberrant beta-catenin signaling in tuberous sclerosis.

The pathology associated with tuberous sclerosis complex (TSC) shows diverse phenotypes that suggest abnormal signaling of multiple pathways. Besides the negative regulatory role of the TSC1/TSC2 proteins on mTOR, we have reported an effect on beta-catenin signaling at the level of the degradation complex in vitro. The TSC1/TSC2 complex associates with GSK3 and Axin and promotes beta-catenin degradation to inhibit Wnt-stimulated TCF/LEF-dependent transcription. Here, we show that beta-catenin and its effectors, cyclin D1 and connexin 43, were up-regulated in TSC-related angiomyolipomas and lymphangioleiomyomatosis. This was supported by the failure of three disease-causing TSC2 missense mutants to inhibit Wnt signaling. Further, the interaction between TSC1/TSC2 and components of the beta-catenin degradation complex was dependent on Wnt stimulation such that binding of tuberin to GSK3 and Axin was reduced in the presence of Wnt whereas the tuberin-Dishevelled interaction was increased. GSK3 activity played a role in regulating the assembly/stability of the degradation complex. Inhibition of GSK3 by lithium chloride reduced its association with TSC1 whereas disruption of GSK3-phosphorylation sites in TSC1 reduced interaction between TSC2 and TSC1. Collectively, our data provide further evidence that beta-catenin signaling plays a role in TSC pathogenesis in vivo and suggest a novel role of GSK3 in modulating the TSC1/TSC2 complex through TSC1 phosphorylation.

Adaptor Proteins, Signal Transducing↗

PubMed2004

The tuberous sclerosis complex genes in tumor development.

The study of hereditary tumor syndromes has laid a solid foundation toward understanding the genetic basis of cancer. One of the latest examples comes from the study of tuberous sclerosis complex (TSC). As a member of the phakomatoses, TSC is characterized by the appearance of benign tumors, most notably in the central nervous system, kidney, heart, lung, and skin. While classically described as "hamartomas," the pathology of the lesions has features suggestive of abnormal cellular proliferation, size, differentiation, and migration. Occasionally, tumors progress to become malignant (i.e., renal cell carcinoma). The genetic basis of this disease has been attributed to mutations in one of two unlinked genes, TSC1 and TSC2. Cells undergo bi-allelic inactivation of either gene to give rise to tumors in a classic tumor suppressor "two-hit" paradigm. The functions of the TSC1 and TSC2 gene products, hamartin and tuberin, respectively, have remained ill defined until recently. Genetic, biochemical, and biologic analyses have highlighted their role as negative regulators of the mTOR signaling pathway. Tuberin, serving as a substrate of AKT and AMPK, mediates mTOR activity by coordinating inputs from growth factors and energy availability in the control of cell growth, proliferation, and survival. Emerging evidence also suggests that the TSC 1/2 complex may play a role in modulating the activity of beta-catenin and TGFbeta. These findings provide novel functional links between the TSC genes and other tumor suppressors responsible for Cowden's disease (PTEN), Peutz-Jeghers syndrome (LKB1), and familial polyposis (APC). Common sporadic cancers such as prostate, lung, colon, endometrium, and breast have ties to these genes, highlighting the potential role of the TSC proteins in human cancers. Rapamycin, a specific mTOR inhibitor, has potent antitumoral activities in preclinical models of TSC and is currently undergoing phase I/II clinical studies.

Biological Transport↗

PubMed2003

The tuberin-hamartin complex negatively regulates beta-catenin signaling activity.

Tuberous sclerosis complex (TSC) is characterized by the formation of hamartomas in multiple organs resulting from mutations in the TSC1 or TSC2 gene. Their protein products, hamartin and tuberin, respectively, form a functional complex that affects cell growth, differentiation, and proliferation. Several lines of evidence, including renal tumors derived from TSC2+/- animals, suggest that the loss or inhibition of tuberin is associated with up-regulation of cyclin D1. As cyclin D1 can be regulated through the canonical Wnt/beta-catenin signaling pathway, we hypothesize that the cell proliferative effects of hamartin and tuberin are partly mediated through beta-catenin. In this study, total beta-catenin protein levels were found to be elevated in the TSC2-related renal tumors. Ectopic expression of hamartin and wild-type tuberin, but not mutant tuberin, reduced beta-catenin steady-state levels and its half-life. The TSC1-TSC2 complex also inhibited Wnt-1 stimulated Tcf/LEF luciferase reporter activity. This inhibition was eliminated by constitutively active beta-catenin but not by Disheveled, suggesting that hamartin and tuberin function at the level of the beta-catenin degradation complex. Indeed, hamartin and tuberin co-immunoprecipitated with glycogen synthase kinase 3 beta and Axin, components of this complex in a Wnt-1-dependent manner. Our data suggest that hamartin and tuberin negatively regulate beta-catenin stability and activity by participating in the beta-catenin degradation complex.

Animals↗

PubMed2002

Multicompartmental distribution of the tuberous sclerosis gene products, hamartin and tuberin.

Mutations of the TSC1 and TSC2 genes give rise to the clinical disorder of tuberous sclerosis characterized by the development of hamartomas predominantly affecting the central nervous system, kidney, skin, lung, and heart. The function of the gene products, hamartin and tuberin, is not well understood but we have previously suggested a role in vesicular transport. To define the subcellular compartment(s) involved with these two proteins, biochemical characterization of hamartin and tuberin was performed in primary tissues and cell lines. Fractionation of cell lysates identified both proteins in the cytosolic, microsomal, and cytoskeletal compartments. In each of these fractions, hamartin and tuberin formed a stable complex in coimmunoprecipitation analyses. Further, they colocalized extensively in discrete, vesicular structures in the cytoplasm. Within the microsomal compartment, hamartin and tuberin behaved as peripheral membrane proteins that associate with the cytosolic leaflet of membranous domains. Immunoisolation of tuberin-bound vesicles using magnetic beads showed an enrichment of rap1, rab5, and caveolin-1, all of which have been found in specialized lipid microdomains, caveolae. Our data suggest that hamartin and tuberin are multicompartmental proteins that partially reside in caveolin-1-enriched structures and potentially affect their signaling.

Animals↗