CAML mediates survival of myc-induced lymphoma cells independent of tail-anchored protein insertion

Jennifer C. Shing, Lonn D. Lindquist, Nica Borgese, Richard J Bram

Research output: Contribution to journalArticle

5 Citations (Scopus)

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-x L 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.

Original languageEnglish (US)
Article number16098
JournalCell Death Discovery
Volume3
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Fingerprint

Cyclophilins
Tail
Lymphoma
Ligands
Calcium
Proteins
Tamoxifen
Endoplasmic Reticulum
Apoptosis
Cell Line
Neoplasms
Calcium Signaling
B-Cell Lymphoma
Histones
Transgenic Mice
Cell Survival
Cell Cycle
Cell Death
Alleles
Amino Acids

ASJC Scopus subject areas

  • Cell Biology
  • Cancer Research
  • Cellular and Molecular Neuroscience
  • Immunology

Cite this

CAML mediates survival of myc-induced lymphoma cells independent of tail-anchored protein insertion. / Shing, Jennifer C.; Lindquist, Lonn D.; Borgese, Nica; Bram, Richard J.

In: Cell Death Discovery, Vol. 3, 16098, 01.01.2017.

Research output: Contribution to journalArticle

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