Abstract
Calcium-modulating cyclophilin ligand (CAML) is an endoplasmic reticulum (ER) protein that functions, along with WRB and TRC40, to mediate tail-anchored (TA) protein insertion into the ER membrane. Physiologic roles for CAML include endocytic trafficking, intracellular calcium signaling, and the survival and proliferation of specialized immune cells, recently attributed to its requirement for TA protein insertion. To identify a possible role for CAML in cancer cells, we generated Eμ-Myc transgenic mice that carry a tamoxifen-inducible deletion allele of Caml. In multiple B-cell lymphoma cell lines derived from these mice, homozygous loss of Caml activated apoptosis. Cell death was blocked by Bcl-2/Bcl-xL overexpression; however, rescue from apoptosis was insufficient to restore proliferation. Tumors established from an Eμ-Myc lymphoma cell line completely regressed after tamoxifen administration, suggesting that CAML is also required for these cancer cells to survive and grow in vivo. Cell cycle analyses of Caml-deleted lymphoma cells revealed an arrest in G2/M, accompanied by low expression of the mitotic marker, phospho-histone H3 (Ser10). Surprisingly, lymphoma cell viability did not depend on the domain of CAML required for its interaction with TRC40. Furthermore, a small protein fragment consisting of the C-terminal 111 amino acid residues of CAML, encompassing the WRB-binding domain, was sufficient to rescue growth and survival of Caml-deleted lymphoma cells. Critically, this minimal region of CAML did not restore TA protein insertion in knockout cells. Taken together, these data reveal an essential role for CAML in supporting survival and mitotic progression in Myc-driven lymphomas that is independent of its TA protein insertion function.
Highlights
Calcium-modulating cyclophilin ligand (CAML) is an endoplasmic reticulum (ER) membrane protein that was originally identified based on its interaction with cyclophilin B.1 It is highly conserved in vertebrates and ubiquitously expressed in mammalian tissues
PH3 may be associated with apoptosis,[18,19] we found that Caml-deleted cells that overexpressed Bcl-2 to block cell death exhibited decreased phospho-histone H3 on serine 10 (pH3) (Figures 4b, 2d and e), indicating that loss of pH3-positive cells did not result from cell death
We aimed to reconcile these distinct roles of CAML in cell viability and TA insertion using Eμ-Myc lymphoma cell lines with tamoxifeninducible deletion of Caml
Summary
Calcium-modulating cyclophilin ligand (CAML) is an endoplasmic reticulum (ER) membrane protein that was originally identified based on its interaction with cyclophilin B.1 It is highly conserved in vertebrates and ubiquitously expressed in mammalian tissues. Calcium-modulating cyclophilin ligand (CAML) is an endoplasmic reticulum (ER) membrane protein that was originally identified based on its interaction with cyclophilin B.1. It is highly conserved in vertebrates and ubiquitously expressed in mammalian tissues. TA proteins are completely synthesized and handed off to chaperone machinery before being targeted to the ER membrane for insertion. These events have been characterized in recent years, with yeast studies having elucidated the GET pathway of TA insertion and mammalian studies continuing to focus on the homologous TMD recognition complex of 40 kDa (TRC40)
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