Disease relevance of BIN1

• Expression of a MYCN-interacting isoform of the tumor suppressor BIN1 is reduced in neuroblastomas with unfavorable biological features [1].
• We propose that loss of BIN1 may contribute to breast cancer progression by eliminating a mechanism that restrains the ability of activated MYC to drive cell division inappropriately [2].
• The purpose of this study is to investigate DNA profile of the BIN1 gene in human hepatoma Hep G2 cells, previously documented with lack of BIN1 expression [3].
• Mechanism for elimination of a tumor suppressor: aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma [4].
• Exon 12A sequences abolished the ability of Bin1 to inhibit malignant transformation by c-Myc or adenovirus E1A [4].

High impact information on BIN1

• Consistent with this likelihood, BIN1 inhibited malignant cell transformation by MYC [5].
• Although BIN1 is expressed in many normal cells, its levels were greatly reduced or undetectable in 14/27 carcinoma cell lines and 3/6 primary breast tumours [5].
• Bin1-induced apoptosis was inhibited in HepG2 cells expressing wild-type NS5A but not NS5A mutant with mutations in the SH3 binding motif [6].
• Deletion and mutation analyses indicated that the SH3 binding motif of HCV NS5A and SH3 domain of Bin1 are essential for interaction [6].
• Human hepatoma (HepG2) cells lacking expression of Bin1 undergo apoptosis upon infection with adeno-Bin1 [6].

Biological context of BIN1

• 9-kilobase fragment from this region was sufficient for basal transcription and transactivation by MyoD, which may account for the high levels of BIN1 observed in skeletal muscle [7].
• The 5'-flanking region of BIN1 is GC-rich and lacks a TATA box but directs transcriptional initiation from a single site [7].
• Structural analysis of the human BIN1 gene. Evidence for tissue-specific transcriptional regulation and alternate RNA splicing [7].
• BIN1 (2q14) encodes multiple isoforms of a Myc-interacting adaptor protein that has features of a tumor suppressor, including the ability to inhibit Myc-mediated cell transformation and to promote apoptosis [1].
• RESULTS: Four predominant BIN1 isoforms resulting from alternative splicing of exon 12A (a neural tissue-specific exon) and exon 13 (a Myc-binding domain encoding exon) were variably expressed in the 56 primary NBs [1].

Anatomical context of BIN1

• In skeletal muscle, amphiphysin II is concentrated around T tubules, while in brain it is concentrated in the cytomatrix beneath the plasmamembrane of axon initial segments and nodes of Ranvier [8].
• Bin1 contains a basic unique amino-acid sequence, Exon10, which interacts with certain phosphoinositides such as phosphatidylinositol-4,5-bisphosphate (PI(4,5)P(2)), to localize to membranes [9].
• In this study, we analyzed the patterns of Bin1 expression in normal melanocytes and melanoma cells at different stages of tumor progression [4].
• A role for the putative tumor suppressor Bin1 in muscle cell differentiation [10].
• Significant levels of Bin1 were observed in undifferentiated C2C12 myoblasts, a murine in vitro model system [10].

Associations of BIN1 with chemical compounds

• Furthermore, BIN1 transcript was identified in additional seven HCC cell lines analyzed [3].
• RNA and immunohistochemical analyses indicated that Bin1 was expressed in most primary tumors, even at slightly elevated levels relative to benign tissues, but that it was frequently missing or inactivated by aberrant splicing in metastatic tumors and androgen-independent tumor cell lines [11].
• Mutational analysis revealed that complex formation is primarily mediated by a proline-rich region in the C-terminal part of NS5A, which interacts with the amphiphysin II Src homology 3 domain [12].
• Upon an AMPH 2 administration, periadolescents exhibited a much lower profile of locomotor hyperactivity than adults, and also failed to show an increase across the course of the session in CORT release, that was observed in adults [13].

Physical interactions of BIN1

• BIN1 is a novel protein that interacts with the functionally critical Myc box regions at the N terminus of the MYC oncoprotein [5].
• RIN3 was also capable of interacting via its Pro-rich domain with amphiphysin II, which contains SH3 domain and participates in receptor-mediated endocytosis [14].
• RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway [14].
• Here, we analyzed these sequences, which we term type II sequences, and show that the (257)LMDLA sequence in rat epsin 1 appears to be a weak clathrin-binding variant of the sequence (417)PWDLW originally found in human amphiphysin II [15].
• Bin2 formed a stable complex in cells with Bin1, but not with amphiphysin, in a BAR domain-dependent manner [16].

Regulatory relationships of BIN1

• BIN1 was expressed in normal and benign cells and tissues but was undetectable in 6/6 estrogen receptor-positive or estrogen receptor-negative carcinoma cell lines examined [2].
• BIN1 inhibits colony formation and induces apoptosis in neuroblastoma cell lines with MYCN amplification [17].

Other interactions of BIN1

• As we reported previously, BIN1 may function to circumvent MycN-mediated apoptosis in NBs with MYCN amplification [1].
• The elucidation of clathrin as a splice-specific binding partner for amphiphysin II begins to address the potential functional role(s) for the multiple amphiphysin II splice variants and further supports an important function for clathrin-amphiphysin interactions in protein targeting during endocytosis [18].
• We conclude that BIN1 is an MYC-interacting protein with features of a tumour suppressor [5].
• Here we found that Exon10 also binds to the src homology 3 (SH3) domain of Bin1 itself, and hence blocks the binding of the SH3 domain to its canonical PxxP ligands, including dynamin [9].
• We also show that the PLCdelta pleckstrin homology domain, another PI(4,5)P(2)-binding module, cannot substitute for Exon10 in Bin1 function in transverse tubule formation, and suggest the importance of the dual biochemical properties of Exon10 in myogenesis [9].

Analytical, diagnostic and therapeutic context of BIN1

• EXPERMENTAL DESIGN: Expression of MYCN, total BIN1, and BIN1 isoforms were determined in 56 primary NBs using the real-time PCR [1].
• Similarly, complete or partial losses of BIN1 were documented in 30/50 (60%) cases of malignant breast tissue analyzed by immuno-histochemistry or RT-PCR [2].
• In immunoprecipitation and Western analyses, cellular BIN1 was identified in human and rodent cells as a monomeric phosphoprotein of M(r) approximately 70,000 [19].
• This effect appeared to be caused by an increase in apoptosis, and was augmented by serum deprivation and concurrent cytotoxic drug therapy in cell culture CONCLUSION: BIN1 inactivation may be necessary for MYCN overexpression to lead to cellular proliferation rather than programmed cell death in neuroblastomas with MYCN amplification [17].
• Southern blot analyses revealed no genetic rearrangements in the BIN1 gene in any of the cell lines studied [3].

References