Ubiquitin-associated (UBA) domain in human fas associated factor 1 inhibits tumor formation by promoting Hsp70 degradation

Jae Jin Lee, Young-Mee Kim, Jaeho Jeong, Duk Soo Bae, Kong Joo Lee

Research output: Contribution to journalArticle

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Abstract

Human Fas associated factor 1 (hFAF1) is a pro-apoptotic scaffolding protein containing ubiquitin-associating (UBA), ubiquitin like 1 and 2 (UBL1, UBL2), and ubiquitin regulatory X (UBX) domains. hFAF1 interacts with polyubiquitinated proteins via its N-terminal UBA domain and with valosin containing protein (VCP) via its C-terminal UBX domain. Overexpression of hFAF1 or its N-terminal UBA domain significantly increases cell death by increasing the degradation of polyubiquitinated proteins. In this study, we investigated whether hFAF1, whose expression level is reduced in cervical cancer, plays a role in tumor formation. We found that HeLa cells overexpressing full-length hFAF1 or the hFAF1 UBA domain alone, significantly suppressed the anchorage independent tumor growth in soft agar colony formation, increased cell death, and activated JNK and caspase 3. Employing UBA-specific tandem immunoprecipitation, we identified moieties specifically interacting with UBA domain of hFAF1, and found that polyubiquitinated Hsp70s are recruited to UBA domain. We also demonstrated that hFAF1 overexpression promotes Hsp70 degradation via the proteasome. We further found that mutating the UBA domain (I41N), as well as knocking down hFAF1 with specific RNAi, abolishs its ability to increase the proteasomal degradation of Hsp70. These findings suggest that hFAF1 inhibits tumor formation by increasing the degradation of Hsp70 mediated via its UBA domain.

Original languageEnglish (US)
Article numbere40361
JournalPloS one
Volume7
Issue number8
DOIs
StatePublished - Aug 2 2012

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ubiquitin
Ubiquitin
Tumors
Degradation
neoplasms
degradation
Neoplasms
Cell death
Ubiquitin C
Cell Death
cell death
scaffolding proteins
Apoptosis Regulatory Proteins
Proteins
uterine cervical neoplasms
Proteasome Endopeptidase Complex
RNA Interference
proteasome endopeptidase complex
HeLa Cells
Immunoprecipitation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Ubiquitin-associated (UBA) domain in human fas associated factor 1 inhibits tumor formation by promoting Hsp70 degradation. / Lee, Jae Jin; Kim, Young-Mee; Jeong, Jaeho; Bae, Duk Soo; Lee, Kong Joo.

In: PloS one, Vol. 7, No. 8, e40361, 02.08.2012.

Research output: Contribution to journalArticle

Lee, Jae Jin ; Kim, Young-Mee ; Jeong, Jaeho ; Bae, Duk Soo ; Lee, Kong Joo. / Ubiquitin-associated (UBA) domain in human fas associated factor 1 inhibits tumor formation by promoting Hsp70 degradation. In: PloS one. 2012 ; Vol. 7, No. 8.
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