Suppression of Neoplastic Transformation and Regulation of Cytoskeleton by Tropomyosins

Abstract

Down regulation of Tropomyosins (TMs) is a consistent biochemical change observed in many transformed cells. Our previous work has demonstrated that Tropomyosin-1 is an antioncogene and it is a class II tumor suppressor. Using ras-transformed murine fibroblasts (DT cells), we have examined the effects of co-expression of two isoforms of TM on cell morphology, cytoskeleton and tumorigenecity. Enhanced expression of TM1, a suppressor of transformation, along with TM2 which is not a tumor suppressor results in the formation of well-organized microfilaments, a morphology that resembles normal fibroblasts, and suppression of tumorigenecity. Tumor formation in vivo was compatible with the persistence of high-level of TM2, but not TM1. Homodimers of TM1 and TM2 were observed in these cells. Thus, restoration of expression of TM1 and TM2 protein in ras-transformed cells suppresses the transformed phenotype with dramatic re-organization of microfilaments. These data show that TM2 cooperates with TM1 in the reorganization of microfilaments, while TM1 is a suppressor of the transformed phenotype.

Tissue factor as an effector of angiogenesis and tumor progression in hematological malignancies

“…Among them, catalase, an antiapoptotic enzyme, 72 and annexin I, a calcium-and phospholipid-binding protein that specifically regulates signaling components of the Ras/MEK/ERK signaltransduction pathway, 73 were found to be expressed in M1, M3 and M5 AML samples at higher levels than in normal monocytes and than in other AML subtypes. On the contrary, tropomyosin, a family of cytoskeletal proteins whose inhibition contribute to the invasive and metastatic properties of cancer cells, 74 was found concomitantly reduced in these AML subtypes. Furthermore, complementary genetic and protein studies demonstrated that blast samples showing increased levels of annexin I and reduced levels of tropomyosin also exhibited enhanced ERK phosphorylation as well as increased expression of both TF and VEGF (Lopez-Pedrera et al Seminars in Proteomics 2005; 2: 215; abstract).…”

Cytoskeletal organization in tropomyosin-mediated reversion of ras-transformation: Evidence for Rho kinase pathway

“…Given the high degree of the malignant nature of DT cells, these changes are expected to be extensive. It should be noted that TM1 and TM2 share extensive homology, yet only TM1 is capable of reorganizing micro®laments and suppressing the Ras-induced transformed phenotype (Braverman et al, 1996;Shah et al, 1998). The properties of micro®laments induced by TM1 in DT cells could signi®cantly di er because the expression of many components is likely to remain repressed due to the continued oncogenic action of Ras.…”

“…To investigate the role of TMs in cellular transformation, we generated several cell lines of DT expressing TM1 (DT/TM1 cells), TM2 (DT/TM2 cells) or both the TMs (DT/TM1-TM2 cells) by introduction of cDNAs encoding TM1, TM2 or both the TMs, respectively (Table 1; Figure 1) (Braverman et al, 1996;Prasad et al, 1991Prasad et al, , 1993Shah et al, 1998). In transformed cells, in addition to TMs, many other proteins including those associated with micro®laments are also suppressed.…”

“…On the contrary, restoration of expression of TM2 protein did not improve the cytoskeleton, and the cells remained transformed, resembling DT cells (Braverman et al, 1996). Coexpression of TM2 with TM1, however, dramatically improved micro®laments, similar to those in normal NIH3T3 cells: DT cells expressing TM1 and TM2 exhibit a revertant phenotype (Shah et al, 1998). It is intriguing that TM1, an actin binding protein reorganizes the cytoskeleton and restores the normal growth phenotype, while the other closely related TMs despite their ability to bind to actin are unable to modulate cytoarchitecture and growth phenotypes (Braverman et al, 1996;Pittenger et al, 1994).…”

“…Other actin binding proteins, such as caldesmon, also in¯uence TM binding to actin to varying degrees (Pittenger et al, 1995). Our e orts to elucidate the causal relationship between tropomyosin expression and cell phenotype have uncovered signi®cant fundamental di erences in the roles of TM isoforms in cell physiology (Braverman et al, 1996;Prasad et al, 1993;Shah et al, 1998).…”