We have discovered p40, the shortest variant of a new human p53 homologue (p40/p51/p63/p73H). We have also found that it plays a role in cancer. Low level amplification of the p40 locus accompanied by RNA and protein overexpression was observed in primary lung cancers, and head and neck cancer cell lines. P40 protein overexpression in primary lung tumors was limited to squamous cell carcinoma, tumors known to harbor a high frequency of p53 mutations. Overexpression of p40 in Rat 1a cells led to an increase in soft agar growth and tumor size in mice. We searched for p40 binding proteins using the yeast two-hybrid system. P53 was the most common binding target of the 1.6.times.10.sup.6 clones screened from a mouse embryonic library. Moreover, coexpression of p40 and p53 led to a decrease in p53 transcriptional activity. Our results support the notion that p40 plays an oncogenic role in human cancer.