MM-1, a c-Myc-binding Protein, Is a Candidate for a Tumor Suppressor in Leukemia/Lymphoma and Tongue Cancer

Abstract

The c-myc oncogene product (c-Myc) is a transcription factor that dimerizes with Max and recognizes the E-box sequence, and it plays key functions in cell proliferation, differentiation, and apoptosis. We previously showed that MM-1 bound to myc box II within the transactivation domain of c-Myc and repressed the E-box-dependent transcriptional activity of c-Myc. Here we report that MM-1 showed features of a tumor suppressor. In an EST data base search for cDNAs homologous to MM-1, we found a frequent substitution of amino acid 157 of MM-1, from alanine to arginine (A157R), and the substitution was observed more in tumor cells than in normal cells. A survey of the A157R mutation of MM-1 in 57 cultured cancer cells and 90 tissues from cancer patients showed that the A157R was present in about 50 -60% of leukemia/lymphoma cells and in more than 75% of squamous cell carcinoma of tongue cancer. Although both the A157R and the wild-type MM-1 bound to c-Myc, only A157R lost the activities to repress both the E-boxdependent transcriptional activity of c-Myc and the myc/ ras cooperative transforming activity in rat 3Y1 cells. Furthermore, the wild-type MM-1, but not A157R, arrested the growth of 3Y1 cells. The human MM-1 gene was mapped at chromosome 12q12-12q13, where many chromosome abnormalities in cancer cells have been reported. The results suggest that MM-1 is a novel candidate for a tumor suppressor that controls the transcriptional activity of c-Myc.

Prefoldin Subunits Are Protected from Ubiquitin-Proteasome System-mediated Degradation by Forming Complex with Other Constituent Subunits

“…MM-1␣ is a novel tumor suppressor that inhibits transcriptional and transforming activities of c-Myc by recruiting the HDAC1 complex via TIF1␤/KAP1, a transcriptional corepressor (12)(13)(14)(15). MM-1␣ is also a subunit of the molecular chaper-FIGURE 7.…”

“…Other PFD Subunits-MM-1␣ has dual functions as a transcriptional modulator through the c-Myc-TIF1␤ pathway (12)(13)(14)(15) and as a subunit, PFD5, of the chaperone prefoldin (2). To examine the behavior of MM-1␣ when PFD complex formation is inhibited, siRNAs targeting PFD2 (siPFD2), MM-1a/PFD5 (siMM-1␣) as a positive control or luciferase (siLuc) as a negative control were transfected into human HeLa, H1299 and HepG2 cells and into mouse embryonic fibroblasts (MEF), Neuro-2a and NIH3T3 cells, and the protein levels of MM-1␣ and PFD2 were examined by Western blotting with respective antibodies.…”

“…We previously identified MM-1␣/PFD5 as a novel protein that binds to the Myc box II located in the N-proximal region of c-Myc to suppress transcription and transformation activities of c-Myc (12,13). We have also shown that MM-1␣ recruits the HDAC complex to c-Myc via TIF-1␤, a corepressor, and that the c-fms gene is a target gene for this pathway (14,15).…”

Two isoforms of human RNA polymerase III with specific functions in cell growth and transformation

“…Strikingly, ectopic expression of RPC32α in the partially transformed IMR90 cell lines increased the expression of genes, including S100A4 (23), replication factor C subunit RFC40 (24), EZRIN (25) and RAC1 (26), that previously have been associated with cell survival, tumor growth and metastasis. Furthermore, ectopic expression of RPC32α reduced expression of genes with reported tumor suppressor activity, such as PREFOLDIN 5 (MM-1) (27) or KLF6 (28), when compared either with partially transformed IMR90 cells or with partially transformed IMR90 cells with ectopically expressed RPC32β ( Fig. 4B and Table S2).…”

Prefoldin Protects Neuronal Cells from Polyglutamine Toxicity by Preventing Aggregation Formation

“…tion, including transcriptional regulation for PFD5 (49,50) and PFD4 (51) and DNA binding activity for PFD1 and PFD2 (52), and that there are some distinctive phenotypes between PFD1-null and PFD5-L110R mice (47,48). PFD5/MM-1 is known to act as a c-MYC-binding protein that suppresses cell growth and transformation independently of the prefoldin complex (49,53). Furthermore, Tang et al (54) have reported that the expression level of PFD5 mRNA was up-regulated in HTTQ300-expressing mice (R6/2) despite the fact that mRNA levels of other subunits were unaffected.…”