Our recent identification of homozygous deletions at 3p21.3 in lung cancer has provided further support for the presence of a tumor suppressor gene in this chromosomal region. As a part of our efforts for positional cloning of a tumor suppressor gene at 3p21.3, we have characterized a transcriptional unit within this region using genomic fragments with interspecies conservation. The identified gene was found to encode a novel integrin alpha subunit, termed alpha RLC, which is closely related to alpha 4 in structure but clearly different from alpha 4 in its expression pattern in the physiological and pathological setting of the lung. This finding and the exact localization of the gene suggest that it is a good candidate for a tumor suppressor gene in lung cancer, but our extensive search covering one third of the gene did not reveal any somatic mutations within the coding region. Interestingly, however, alpha RLC was abundantly expressed in fetal lung and lung cancers, particularly small cell lung cancers (SCLC). Its aberrant upregulation in the SCLC samples, both cell lines and primary tumors, which might have been caused by a yet unidentified mutations or by deletions of other gene, and its homology to alpha 4, which is thought to play a role in metastasis, suggest that altered alpha RLC expression may contribute to the acquisition of malignant phenotypes of this type of lung cancer.