Sequence-specific DNA Binding and Transcriptional Regulation by the Promyelocytic Leukemia Zinc Finger Protein

Abstract

Chromosomal translocation t(11;17)(q23;21) is associated with a retinoic acid-resistant form of acute promyelocytic leukemia. The translocation fuses the RAR␣ gene to the PLZF gene, resulting in the formation of reciprocal fusion proteins, hypothesized to play prominent roles in leukemogenesis. Promyelocytic leukemia zinc finger (PLZF) encodes a transcription factor with nine Krü ppel-like zinc fingers, seven of which are retained in the t(11;17) fusion protein RAR␣-PLZF. We identified a specific DNA-binding site for the PLZF protein and showed that PLZF binds to this site through its most carboxyl seven zinc fingers. In co-transfection experiments, PLZF repressed transcription through its cognate binding site. This repression function of PLZF was mapped to two regions on the protein, including the evolutionarily conserved POZ domain. In contrast, the RAR␣-PLZF protein activated transcription of a promoter containing a PLZF response element. These results suggest that RAR␣-PLZF, generated in acute promyelocytic leukemia, is an aberrant transcription factor that can deregulate the expression of PLZF target genes and contribute to leukemogenesis.

Retinoic acid, but not arsenic trioxide, degrades the PLZF/RARα fusion protein, without inducing terminal differentiation or apoptosis, in a RA-therapy resistant t(11;17)(q23;q21) APL patient

“…The third explanation is an implication of the reciprocal RARa/PLZF product, whose mRNA is found in all t(11;17) patients. This putative reciprocal fusion protein contains the ®ve C-terminal zinc ®ngers, was recently shown to be transforming and to bind DNA (Li et al, 1997;Sitterlin et al, 1997), and could thus, through competition with wild type PLZF, alter normal PLZF function. Indeed, normal PLZF could be delocalized by either PLZF/RARa or PML/RARa; in the t(11;17) cases, the few normal PLZF polypeptides which are not trapped by PLZF/ RARa could be chased from their recognition sites by RARa/PLZF.…”

“…Thus far this di erence was attributed to the divergent N-terminal fusion partners. Through its POZ domain, PLZF is a transcriptional repressor (Li et al, 1997), and was recently shown to bind the SMRT co-repressor (Dhordain et al, 1997;Hong et al, 1997). PLZF, like PML, displays growth suppressive properties and has a nuclear speckled localization, which upon fusion to RARa becomes microspeckled .…”

Deregulation of NPM and PLZF in a variant t(5;17) case of acute promyelocytic leukemia

“…It is of interest that RARa-PLZF appears to be expressed in all t(11;17)(q23;q21) patients, and that it also contains the N-terminal RARa transactivating domain juxtaposed to a DNA binding domain. Since RARa-PLZF seems to play a role in APL pathogenesis by acting as a trans dominant activator of PLZF responsive genes (Li et al, 1997); Sitterlin et al, 1997), it is possible that RARa-NPM might also act as a second, dominant interfering gene in t(5;17)-associated APL. In this study, as well as in the previous t(5;17) APL report, the N-terminal portion of NPM is joined to the essential functional domains of RARa.…”

“…Nearly 100% of APL cases are associated with a t(15;17)(q22;q21) translocation that fuses RARa to the promyelocytic leukemia gene (PML) at chromosome 15q22 (de The et al, 1990(de The et al, , 1991Alcalay et al, 1991;Goddard et al, 1991;Kakizuka et al, 1991). The resulting PML-RARa gene is invariably expressed in t(15;17) APL (Castaigne et al, 1992;Grignani et al, 1994) in comparison to the reciprocal RARa-PML gene which is expressed in approximately 80% of cases (Alcalay et al, 1992;Borrow et al, 1992;Grimwade et al, 1996;Li et al, 1997).…”

Human endogenous retrovirus protein cORF supports cell transformation and associates with the promyelocytic leukemia zinc finger protein

“…It recognizes speci®c DNA sequences via its C-terminal zinc ®nger domain consisting of nine KruÈ ppel-like C2H2 elements (Li et al, 1997). However, PLZF does not function as a transactivator; rather, target genes are suppressed upon DNA binding by the interaction of the N-terminal POZ domain with the co-repressors N-CoR, SMRT, Sin3A and HDAC1 (histone deacetylase 1; Hong et al, 1997;He et al, 1998;Lin et al, 1998;Grignani et al, 1998;David et al, 1998).…”