Disease relevance of MAD1L1

• We placed a mutant truncated MAD1L1, found in a lymphoma sample, into HOS, Ht161 and SJSA cell lines and found that it was less inhibitory than wild type MAD1L1 at decreasing cell proliferation [1].
• We examined a total of 44 cell lines (hematopoietic, prostate, osteosarcoma, breast, glioblastoma and lung) and 133 fresh cancer cells (hematopoietic, prostate, breast and glioblastoma) for alterations of MAD1L1 by RT-PCR-SSCP and nucleotide sequencing [1].
• In searching for cellular targets of the HTLV-I oncoprotein Tax, we identified TXBP181, which we characterized as the human homolog of yeast mitotic checkpoint MAD1 protein [2].
• Gain of a region on 7p22.3, containing MAD1L1, is the most frequent event in small-cell lung cancer cell lines [3].
• The NMR structure of the complex formed by the PAH2 domain of mammalian Sin3A with the transrepression domain (SID) of human Mad1 reveals that both domains undergo mutual folding transitions upon complex formation generating an unusual left-handed four-helix bundle structure and an amphipathic alpha helix, respectively [4].

Psychiatry related information on MAD1L1

• Identification and characterization of rapidly dividing U937 clones with differential telomerase activity and gene expression profiles: role of c-Myc/Mad1 and Id/Ets proteins [5].

High impact information on MAD1L1

• The roles of MAD1, MAD2 and MAD3 in meiotic progression and the segregation of nonexchange chromosomes [6].
• Expression of either Tax or a transdominant-negative TXBP181 results in multinucleated cells, a phenotype consistent with a loss of HsMAD1 function [2].
• HsMAD1 functions as a homodimer [2].
• Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1 [2].
• It has now been established that RZZ is directly or indirectly responsible for both Mad1-Mad2 recruitment to unattached kinetochores and its subsequent shedding from kinetochores following MT attachment, and thus is involved in both the activation and inactivation of the checkpoint [7].

Biological context of MAD1L1

• MAD1L1 is a checkpoint gene, and its dysfunction is associated with chromosomal instability [1].
• The gene FTSJ2 is located on chromosome 7p22 between MAD1L1 and NUDT1 [8].
• Mitotic checkpoint locus MAD1L1 maps to human chromosome 7p22 and mouse chromosome 5 [9].
• We show that RNAi-mediated suppression of Mad1 function in mammalian cells causes loss of Mad2 kinetochore localization and impairment of the spindle checkpoint [10].
• Mad1 was first identified in budding yeast as an essential component of the checkpoint system that monitors spindle assembly in mitosis and prevents premature anaphase onset [11].

Anatomical context of MAD1L1

• Most significantly, a partial repression of either MAD1 or MAD2 confers resistance to nocodazole, a drug that inhibits microtubule attachment [12].
• The localization of HsMad1 to nuclear pore complexes suggests an alternate, non-mitotic role for the Mad1/Tax interaction in the viral transformation of cells [11].
• In contrast, Mad1 protein was induced and bound to the hTERT promoter in differentiated HL60 cells [13].
• Like MAD1, NEK2A is localized to HeLa cell kinetochore of mitotic cells [14].
• These findings demonstrate that MAD1 regulates cell cycle withdrawal during a late stage of granulocyte differentiation, and suggest that the relative levels of MYC versus MAD1 mediate a balance between cell proliferation and terminal differentiation [15].

Associations of MAD1L1 with chemical compounds

• Furthermore, this mutant impaired the mitotic checkpoint as shown by decreased mitotic indices in HOS cells expressing mutant MAD1L1 after culture with the microtubule-disrupting agent, nocodazole [1].
• In contrast, sensitivity to clinically relevant drugs like taxol or monastrol that inhibit the generation of tension across kinetochores is not modulated by partial downregulation of MAD1, suggesting a functional bifurcation of spindle checkpoint dependent apoptotic pathways [12].
• This chimeric repressor was engineered by fusing the tetracycline repressor (TetR) with an mSin3-interacting domain of human Mad1 and was shown to bind the tetO(2) element with high affinity, and its binding was efficiently abrogated by doxycycline [16].
• This clearly suggests that Asp 112 plays a crucial role in the molecular recognition between Max and Mad1 [17].
• Mad1-expressing cells were further found to be reduced in cell size in all phases of the cells cycle and particularly in response to RA-induced differentiation [18].

Physical interactions of MAD1L1

• Mad2 also undergoes a similar striking structural change upon binding to a Mad1 or Cdc20 binding motif peptide [10].
• NEK2A interacts with MAD1 and possibly functions as a novel integrator of the spindle checkpoint signaling [14].
• We also found that in mitotic cells Mad1 co-immunoprecipitated with Plk1 [19].

Regulatory relationships of MAD1L1

• These observations indicate that c-myc and mad1 can regulate the hTERT transcript in a different manner in hTERT positive cells, but not in normal cells [20].
• Mad2 phosphorylation regulates its association with Mad1 and the APC/C [21].
• This required the development of a novel non-antibody method to induce precocious anaphase onset in vivo by using a bacterially expressed fragment of the spindle checkpoint protein Mad1 capable of activating the APC/C, called GST-Mad1F10 [22].
• KLF11 is a biochemical paradigm for a subset of proteins that repress transcription via a Mad1-like mSin3A interacting domain (SID) [23].

Other interactions of MAD1L1

• Among the transcript regulation factors of hTERT, c-myc and mad1 are well known [20].
• Role of Hec1 in spindle checkpoint signaling and kinetochore recruitment of Mad1/Mad2 [24].
• We conclude that expression changes in mitotic arrest deficiency genes (MAD1, MAD2L1, and MAD2L2) play a role in renal carcinogenesis characterized by multiple numerical chromosome abnormalities [25].
• Mad1 also arrested tumor growth and downregulated hTERT expression and telomerase activity in bladder cancer xenograft BALB/c nude mice [26].
• Assembly of b/HLH/z proteins c-Myc, Max, and Mad1 with cognate DNA: importance of protein-protein and protein-DNA interactions [27].

Analytical, diagnostic and therapeutic context of MAD1L1

• Chromatin immunoprecipitation assay revealed that p53, histone deacetylase 1, and co-repressor mSin3a associated with the MAD1 promoter in vivo [28].
• The growth characteristics and malignant potential of two Mad1 transfectants of the FEM human melanoma cell line, overexpressing Mad1 stably and the respective vector control were analysed both in vitro and in a nude mice xenograft model in vivo [29].
• RT-PCR method was employed to detect the influence of EGCG on the expressions of hTERT, c-myc, p53 and mad1 genes in sensitive cancer cell line [30].
• Furthermore, a Mad1-induced block of S-phase progression can be overcome by trichostatin A, as shown in microinjection experiments [31].
• Hepatocyte transplantation improves survival in mice with liver toxicity induced by hepatic overexpression of Mad1 transcription factor [32].

References