Internal translation of the connexin 43 transcript
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Open Access
Internal translation of the connexin 43 transcript Clàudia Salat-Canela, Marta Sesé, Cristina Peula, Santiago Ramón y Cajal and Trond Aasen*
Abstract Background: Connexin 43 (Cx43), the most widely expressed gap junction protein, is associated with a number of physiological and pathological conditions. Many functions of Cx43 have been shown to be independent of gap junction formation and only require the expression of Cx43 C-terminal fragments. Recent evidence demonstrated that naturally occurring C-terminal isoforms can be generated via internal translation. Findings: Here, we confirm that C-terminal domains of Cx43, particularly the major 20-kDa isoform, can be independently generated and regulated by internal translation of the same single GJA1 gene transcript that encodes full-length Cx43. Through direct RNA transfection experiments, we provide evidence that internal translation is not due to a bona fide cap-independent IRES-mediated mechanism, as upstream ribosomal scanning or translation is required. In addition to the mTOR pathway, we show for the first time, using both inhibitors and cells from knockout mice, that the Mnk1/2 pathway regulates the translation of the main 20-kDa isoform. Conclusions: Internal translation of the Cx43 transcript occurs but is not cap-independent and requires translation upstream of the internal start codon. In addition to the PI3K/AKT/mTOR pathway, the major 20-kDa isoform is regulated by the Mnk1/2 pathway. Our results have major implications for past and future studies describing gap junction-independent functions of Cx43 in cancer and other pathological conditions. This study provides further clues to the signalling pathways that regulate internal mRNA translation, an emerging mechanism that allows for increased protein diversity and functional complexity from a single mRNA transcript. Keywords: Gap junction, Connexin 43, IRES, Mnk, mTOR, Cap-dependent, Internal translation
Findings Gap junctional intercellular communication, which allows the exchange of small ions and messengers between cells, is crucial for tissue development and homeostasis [1,2]. Connexin 43 (Cx43)—the most widely expressed gap junction protein—is associated with a number of pathological conditions, including cardiac, skin, neurological conditions, as well as developmental disorders and cancer [2]. Numerous studies have demonstrated that Cx43 has several junction-independent functions, many of which can be attributed solely to the C-terminus. For example, the Cx43 C-terminus has been shown to mediate neuroprotection during stroke [3], to negatively modulate neuronal differentiation [4], to augment p38-mediated cell migration [5], and to regulate cytoskeletal changes in glioma cells [6]. A naturally occurring cytoplasmic * Correspondence: [email protected] Molecular Pathology, Hospital Universitari Vall d’Hebron - Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Passeig Vall d’Hebron 119-129, Barcelona 08035, Spain
C-terminal fragment of Cx43, ~20 kDa in size
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