The nuclear pore complex (NPC) consists of a conserved set of ~30 different proteins, termed nucleoporins, and serves as a gateway for the exchange of materials between the cytoplasm and nucleus. Tpr (translocated promoter region) is a component of NPC that presumably localizes at intranuclear filaments. Here, we show that Tpr knockdown caused a severe reduction in the number of nuclear pores. Furthermore, our electron microscopy studies indicated a significant reduction in the number of inner nuclear filaments. In addition, Tpr siRNA treatment impaired cell growth and proliferation compared to control siRNA-treated cells. In Tpr-depleted cells, the levels of p53 and p21 proteins were enhanced. Surprisingly, Tpr depletion increased p53 nuclear accumulation and facilitated autophagy. Our study demonstrates for the first time that Tpr plays a role in autophagy through controlling HSP70 and HSF1 mRNA export, p53 trafficking with karyopherin CRM1, and potentially through direct transcriptional regulation of autophagy factors.