UCHL5 is a member of the UCH enzyme family and contains a conserved catalytic domain and a nonconserved extended C-terminal tail.The activity of UCHL5 was significantly increased in 76% of the tumors analyzed. UCHL5 sequentially removes ubiquitin from the distal end of the lys48-linked polyubiquitin chain and has the potential to rescue ubiquitinated substrates from proteasomal degradation. UCHL5 was active in 92% (24 of 26) of the cervical carcinoma biopsies, and in 100% of 8 cervical carcinoma cell lines, of which 6 were HPV-positive and 2 were HPV-negative. UCHL5 activity level did not correlate with the clinical stage of the tumors or the presence of metastases.Uchl5 overexpression increases Tgfbr1-dependent transcription. Knockdown of Uchl5 expression by RNA interference abrogated Tgf-beta-dependent transcription.