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Programmed cell death (PDCD)5 is cloned from human leukemia cell line TF-1. PDCD5 is one of the members of the programmed cell death protein family that is frequently involved in tumor growth and apoptosis. To investigate the molecular and cellular functions of PDCD5, the present study established a PDCD5 stably overexpressing A431 cell line and examined the role of PDCD5 in cell proliferation, cell cycle progression and apoptosis. The data demonstrated that overexpression of PDCD5 significantly inhibited cell proliferation, induced cell cycle arrest at G2/M phase and apoptosis in A431 cells. The expression profiles of certain key regulators of these cellular events were further investigated, including P53, B cell lymphoma (BCL)-2, BCL-2 associated X protein (BAX) and caspase (CASP)3. The data demonstrated that at the transcript and protein levels, P53, BAX and CASP3 were all upregulated in the PDCD5 stably overexpressing A431 cells whereas BCL-2 was downregulated, indicating that PDCD5 acts as an important upstream regulator of P53, BCL-2, BAX and CASP3. The data suggest that PDCD5 regulates cell proliferation, cell cycle progression and apoptosis in A431 cells. PDCD5 may be a novel tumor suppressor gene, and may be potentially used for cancer treatment in the future.