The chromosome 3p21.3-encoded gene, LIMD1, is a critical tumor suppressor involved in human lung cancer development

Tyson V. Sharp, Ahmad Al-Attar, Daniel E. Foxler, Li Ding, Thomas Q.De A. Vallim, Yining Zhang, Hala S. Nijmeh, Thomas M. Webb, Andrew G. Nicholson, Qunyuan Zhang, Aldi Kraja, Ian Spendlove, John Osborne, Elaine Mardis, Gregory D. Longmore

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Loss of heterozygosity (LOH) and homozygous deletions at chromosome 3p21.3 are common in both small and nonsmall cell lung cancers, indicating the likely presence of tumor suppressor genes (TSGs). Although genetic and epigenetic changes within this region have been identified, the functional significance of these changes has not been explored. Concurrent protein expression and genetic analyses of human lung tumors coupled with functional studies have not been done. Here, we show that expression of the 3p21.3 gene, LIMD1, is frequently down-regulated in human lung tumors. Loss of LIMD1 expression occurs through a combination of gene deletion, LOH, and epigenetic silencing of transcription without evidence for coding region mutations. Experimentally, LIMD1 is a bona fide TSG. Limd1-/- mice are predisposed to chemical-induced lung adenocarcinoma and genetic inactivation of Limd1 in mice heterozygous for oncogenic K-RasG12D markedly increased tumor initiation, promotion, and mortality. Thus, we conclude that LIMD1 is a validated chromosome 3p21.3 tumor-suppressor gene involved in human lung cancer development. LIMD1 is a LIM domain containing adapter protein that localizes to E-cadherin cell-cell adhesive junctions, yet also translocates to the nucleus where it has been shown to function as an RB corepressor. As such, LIMD1 has the potential to communicate cell extrinsic or environmental cues with nuclear responses.

Original languageEnglish
Pages (from-to)19932-19937
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number50
DOIs
StatePublished - Dec 16 2008

Keywords

  • Epigenetic silencing
  • K-Ras G12D
  • LIM proteins
  • Retinoblastoma
  • Tumor suppressor genes

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