Nucleoplasmic lamins define growth-regulating functions of lamina-associated polypeptide 2 alpha in progeria cells

A-type lamins are components of the peripheral nuclear lamina but also localize in the nuclear interior in a complex with lamina-associated polypeptide (LAP) 2 alpha. Loss of LAP2 alpha and nucleoplasmic lamins in wild-type cells increases cell proliferation, but in cells expressing progerin (a mutant lamin A that causes Hutchinson-Gilford progeria syndrome), low LAP2 alpha levels result in proliferation defects. Here, the aim was to understand the molecular mechanism governing how relative levels of LAP2 alpha, progerin and nucleoplasmic lamins affect cell proliferation. Cells from progeria patients and inducible progerin-expressing cells expressing low levels of progerin proliferate faster than wild-type or lamin A-expressing control cells, and ectopic expression of LAP2 alpha impairs proliferation. In contrast, cells expressing high levels of progerin and lacking lamins in the nuclear interior proliferate more slowly, and ectopic LAP2 alpha expression enhances proliferation. However, simultaneous expression of LAP2 alpha and wildtype lamin A or an assembly-deficient lamin A mutant restored the nucleoplasmic lamin A pool in these cells and abolished the growth-promoting effect of LAP2 alpha. Our data show that LAP2 alpha promotes or inhibits proliferation of progeria cells depending on the level of A-type lamins in the nuclear interior.