Generation and Characterization of LANP/pp32 Null Mice

Abstract

The leucine-rich acidic nuclear protein (LANP) belongs to a family of evolutionarily conserved proteins that are characterized by an amino-terminal domain rich in leucine residues followed by a carboxy-terminal acidic tail. LANP has been implicated in the regulation of a variety of cellular processes including RNA transport, transcription, apoptosis, vesicular trafficking, and intracellular signaling. Abundantly expressed in the developing cerebellum, this protein has also been hypothesized to play a role in cerebellar morphogenesis. LANP has been implicated in disease biology as well, both as a mediator of toxicity in spinocerebellar ataxia type 1 and as a tumor suppressor in cancers of the breast and prostate. To better understand the function of this multifaceted protein, we have generated mice lacking LANP. Surprisingly, these mice are viable and fertile. In addition we could not discern any derangements in any of the major organ systems, including the nervous system, which we have studied in detail. Overall our results point to a functional redundancy of LANP's function, most likely provided by its closely related family members.Leucine-rich acidic nuclear protein (LANP or pp32 [for phosphoprotein with a molecular mass of 32 kDa]) is a member of the leucine-rich family of proteins (16-18). These proteins are involved in a variety of pathways including signaling, protein degradation, cytoskeletal dynamics, and morphogenesis, presumably based on the ability of the leucine-rich repeat (LRR) domains to serve as adapter sites for protein-protein interactions.For LANP, the hydrophobic LRRs reside in its N-terminal domain, giving LANP a globular head domain. The C-terminal domain, on the other hand, is extended and hydrophilic, engaging interactors by virtue of its ionic interactions (23,27,30,31).Several proteins have extensive homology to LANP, both in displaying LRRs in their N terminal domains and in demonstrating extended acidic tail domains. These proteins represent true LANP family members that have probably arisen by gene duplication. The nomenclature of LANP family members is confusing because the same protein has been given more than one name based on the context of isolation. Thus APRIL, an acronym derived from A protein rich in leucines, is also known as PAL-31, for proliferation-associated leucine-rich protein, MW 31kDa, and SSP-29, for silver-stainable protein with a molecular mass of 29 kDa (24,25,41). CPD1 (cerebellar postnatal development protein 1), another LANP family member, has been called LANP-like protein (LANP-L) (21, 28). Two human homologues of LANP/pp32 have been called pp32r1 and pp32r2 to signify that they are related (14,15). Besides having homology with these proteins, LANP family members also have limited homology to template-activating factor (TAF) proteins, TAF-1 alpha and beta (the latter being the product of the SET oncogene). The TAF-1 proteins, like the LANP family members, demonstrate long acidic C-terminal domains but, unlike LANP, do not display LRRs in their Nterminal doma...

pp32/PHAPI determines the apoptosis response of non-small-cell lung cancer

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Variation at the ANP32A gene is associated with risk of hip osteoarthritis in women

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Tumor suppressor pp32 represses cell growth through inhibition of transcription by blocking acetylation and phosphorylation of histone H3 and initiating its proapoptotic activity

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