Biomedical subjects
Publications and source records attributed to R A Screaton.
Anoikis is defined as apoptosis that is induced by inadequate or inappropriate cell-matrix interactions. It is involved in a wide diversity of tissue-homeostatic, developmental and oncogenic processes. The central problem of anoikis is to understand how integrin-mediated cell adhesion signals control the apoptotic machinery. In particular, the initiation of the caspase cascade in anoikis remains to be explained.
Ectopic expression of various members of the human carcinoembryonic antigen (CEA) family of intercellular adhesion molecules in murine myoblasts either blocks (CEA, CEACAM6) or allows (CEACAM1) myogenic differentiation. These surface glycoproteins form a subset of the immunoglobulin (Ig) superfamily and are very closely related, but differ in the precise sequence of their external domains and in their mode of anchorage to the cell membrane. CEA and CEACAM6 are glycophosphatidyl-inositol (GPI) anchored, whereas CEACAM1 is transmembrane (TM) anchored. Overexpression of GPI-linked neural cell adhesion molecule (NCAM) p125, also an adhesion molecule of the Ig superfamily, accelerates myogenic differentiation. The molecular requirements for the myogenic differentiation block were investigated using chimeric constructs in which the COOH-terminal hydrophobic domains of CEA, CEACAM1, and NCAM p125 were exchanged. The presence of the GPI signal sequence specifically from CEA in the chimeras was sufficient to convert both CEACAM1 and NCAM into differentiation-blocking proteins. Conversely, CEA could be converted into a neutral protein by exchanging its GPI anchor for the TM anchor of CEACAM1. Since the external domains of CEA, CEACAM1, and NCAM can all undergo homophilic interactions, and mutations in the self-adhesive domains of CEA abrogate its differentiation-blocking activity, the structural requirements for differentiation-inhibition are any self-adhesive domains attached to the specific GPI anchor derived from CEA. We therefore suggest that biologically significant functional information resides in the processed extreme COOH terminus of CEA and in the GPI anchor that it determines.
Human carcinoembryonic antigen (CEA), a widely used tumor marker, and CEACAM6 [formerly nonspecific cross-reacting antigen (NCA)] are up-regulated in many types of human cancers, whereas family member CEACAM1 [formerly biliary glycoprotein (BGP)] is usually down-regulated. Deregulated overexpression of CEA/CEACAM6 but not CEACAM1 can inhibit the differentiation and disrupt the polarization and tissue architecture of many different types of cells. In this report, we show that CEA and CEACAM6, but not CEACAM1, markedly inhibit the apoptosis of cells when deprived of their anchorage to the extracellular matrix, a process known as anoikis. By blocking this tissue architecture surveillance mechanism, the architectural perturbation initiated by CEA/CEACAM6 can thus be maintained.
Carcinoembryonic antigen (CEA) is a tumor marker that is overexpressed in many human cancers and functions in vitro as a homotypic intercellular adhesion molecule. We have investigated the possibility of synergy between CEA, v-Myc, and Bcl-2 in the transformation of cells with differentiation capacity. We find that v-Myc increases the cell division rate and maximum density of rat L6 myoblasts but also markedly stimulates both apoptosis and surprisingly, differentiation, thus preventing transformation. The superposition of Bcl-2 blocks the apoptotic stimulation of v-Myc and independently promotes further cell division at confluence, but still allows differentiation. The further expression of CEA has a dominant effect in blocking differentiation, regardless of the presence of the other activated oncogenes, generating cells that enter a reversible quiescent G0-like state in medium promoting differentiation. Transfectants expressing CEA with or without v-myc and bcl-2 allow the emergence of cells with the property of heritable, efficient, anchorage-independent growth in soft agar and the ability to markedly reduce the latency for tumor formation in nude mice. We propose that by prolonging cell survival in the presence of differentiation signals, CEA represents a novel class of dominant differentiation-blocking oncogene.
The immunoglobulin superfamily represents an ancient, highly diversified group of cell surface and extracellular molecules responsible for a wide range of molecular and cellular recognition functions. The human carcinoembryonic antigen (CEA) subfamily of the immunoglobulin superfamily presents evidence of continuing diversification of the immunoglobulin family, in that some of its members, including CEA itself and nonspecific cross-reacting antigen (NCA), are expressed only in primates and not in rodents. These "new" members are glycophosphatidylinositol linked to the external cell membrane and are up-regulated in cancer, unlike members present in both rodents and primates, i.e., biliary glycoprotein (BGP), which are transmembrane linked and down-regulated in cancer. CEA, NCA, and BGP have all been shown to function in vitro as intercellular adhesion molecules. We show here that the properties of adhesion are radically different, in that BGP-mediated adhesion is reversibly Ca2+ and Mg2+ dependent, temperature dependent, and ATP inhibitable, whereas CEA- and NCA-mediated adhesion is the opposite in all aspects. Also, the novel double-reciprocal, antiparallel binding observed for CEA-CEA interactions is not seen for BGP. Finally, the myogenic differentiation block demonstrated for the ectopic expression of CEA in myoblasts was also observed for NCA but not for BGP, which is consistent with the changes in expression seen in cancer. The appearance of new CEA family members with such different properties is discussed in the context of evolution and cancer.