Lamina-associated polypeptide (LAP)2α and other LEM proteins in cancer biology

Abstract

The LEM proteins comprise a heterogeneous family of chromatin-associated proteins that share the LEM domain, a structural motif mediating interaction with the DNA associated protein, Barrier-to-Autointegration Factor (BAF). Most of the LEM proteins are integral proteins of the inner nuclear membrane and associate with the nuclear lamina, a structural scaffold of lamin intermediate filament proteins at the nuclear periphery, which is involved in nuclear mechanical functions and (hetero-)chromatin organization. A few LEM proteins, such as Lamina-associated polypeptide (LAP)2α and Ankyrin and LEM domain-containing protein (Ankle)1 lack transmembrane domains and localize throughout the nucleoplasm and cytoplasm, respectively. LAP2α has been reported to regulate cell proliferation by affecting the activity of retinoblastoma protein in tissue progenitor cells and numerous studies showed upregulation of LAP2α in cancer. Ankle1 is a nuclease likely involved in DNA damage repair pathways and single nucleotide polymorphisms in the Ankle1 gene have been linked to increased breast and ovarian cancer risk. In this review we describe potential mechanisms of the involvement of LEM proteins, particularly of LAP2α and Ankle1 in tumorigenesis and we provide evidence that LAP2α expression may be a valuable diagnostic and prognostic marker for tumor analyses.

Figure 1

Schematic overview of the mammalian LEM-protein family. Protein localization and domains are indicated.

Figure 2

LAP2α, lamin A/C and pRb interact directly and may form a trimeric complex. Domain organization of human LAP2α and pRb and interaction domains are shown.

Figure 3

The pRb/E2F pathway regulates cell cycle progression. The scheme depicts major upstream regulators of pRb and downstream effectors, as well as important pro-proliferative and anti-proliferative feedback mechanisms upon transition from a resting (G0) to a proliferating state and during G1 to S-phase progression. The potential role of nucleoplasmic LAP2α-lamin A/C complexes in the pRb regulatory network is indicated.

Figure 4

Hypothetical model of the functions of the peripheral lamina and the nucleoplasmic LAP2α-lamin A/C complex in the regulation of the pRb/E2F pathway in non-proliferating and proliferating cells. In arrested cells the lamina may tether and stabilize hypophosphorylated pRb and serve as platform for efficient PP2A-dependent dephosphorylation of phospho-pRb. The nucleoplasmic LAP2α-lamin A/C complex activates repressor activity of pRb leading to E2F target gene repression. In proliferating cells, ERK may release pRb from the lamina, favoring its cdk-mediated phosphorylation. LAP2α-lamin A/C complexes dissociate from phospho-Rb, allowing E2F activation and E2F target gene expression.

Figure 5

LAP2α transiently localizes to telomeric regions during late anaphase-telophase (top) and is detected on the chromosome tips in metaphase spreads (bottom). Confocal fluorescence images showing the localization of ectopic, fluorescently tagged LAP2α and Histone 2B (upper panel) or stained for LAP2α and DNA (courtsey of T. Dechat and A. Gajewski, MFPL). Bars, 5μm. Arrow indicates localization of YFP-LAP2α at chromosome tips in late anaphase. Right panel shows a hypothetical involvement of LAP2α in telomere stability based on recently reported protein interactions. See text for details.