The main research focus of our lab has centered on the role of the mammalian orthologs of the Drosophila dREAM complex in cell cycle regulation. The two projects currently underway can be summarized as follows:

Understanding the mechanisms that govern cell cycle progression is important for the development of novel therapeutic agents against cancer. The G1 phase is a critical crossroad where positive and negative regulatory signals converge to control cell cycle progression. The family of pocket proteins is responsible for restricting cell cycle progression via the formation of repressor complexes with E2F and DP family members, which result in the inhibition of E2F target genes. We cloned a novel gene, originally named BARA, currently termed human Mip/LIN-9, which regulates cell cycle progression. Our studies demonstrate that deletion of the first 84 amino acids of Mip/LIN-9 (Mip/LIN-9?84) corrects the CDK4 null phenotype. Therefore, Mip/LIN-9, like the pocket proteins pRB, p107 and p130, is negatively regulated by CDK4. Interestingly, the correction of the CDK4 null phenotype is accompanied by a restoration of the expression of genes such as E2F1, E2F3, and cyclin E suggesting that Mip/LIN-9 participates in the regulation of E2F target genes required for the G1/S transition. This is further supported by the finding that Mip/LIN-9 interacts with two members of the pocket family, p107 and p130. The objectives of this project are: 1) To characterize the mechanism that leads to the correction of the CDK4 null phenotype by the mutation Δ84 of Mip/LIN-9. 2) To test the hypothesis that Mip/LIN-9 is part of the transcriptional repressor complex formed by p107,130/E2F4,5/DPs and that its interaction with other members of the complex is required for the regulation of the expression of E2F target genes responsible for cell cycle progression.

In Drosophila, the homolog of Mip/LIN-9, Mip130, is part of a large complex termed dREAM (drosophila RB, E2F and Myb) that includes pocket proteins, repressor forms of E2F, B-Myb and B-Myb-interacting proteins termed Mip(s). This complex inhibits transcription of specific genes and duplication of specific genomic regions. Our data suggest that the mammalian equivalent of Mip130, Mip/LIN-9, forms a complex with pocket proteins, E2Fs and B-Myb; however, unlike the Drosophila counterpart, not all proteins are in the same complex simultaneously. For example, Mip/LIN-9 interacts with p107, p130 and E2F4 in G0 and early G1, and with B-Myb in late G1 and S phase. Moreover, while the complex that Mip/LIN-9 forms with E2F4 and p107 or p130 has a repressor effect, the interaction with B-Myb is responsible for the induction of critical S-phase and mitotic genes such as cyclin A, cyclin B and CDK1.

Additionally, we are characterizing the role of mammalian Mip40/LIN-37 and Mip120/LIN-54 whose orthologs are also part of the dREAM and DRM complexes in Drosophila and C. elegans, respectively.

• Pilkinton M, Sandoval R, Colamonici OR. Mammalian Mip/LIN-9 interacts with either the p107, p130/E2F4 repressor complex or B-Myb in a cell cycle-phase-dependent context distinct from the Drosophila dREAM complex. Oncogene. 2007 Jun 11; [Epub ahead of print]
  PMID: 17563750 [PubMed - as supplied by publisher]


• Pilkinton M, Sandoval R, Song J, Ness SA, Colamonici OR. Mip/LIN-9 regulates the expression of B-Myb and the induction of cyclin A, cyclin B, and CDK1. J Biol Chem. 2007 Jan 5;282(1):168-75.
  Epub 2006 Nov 10. PMID: 17098733 [PubMed - indexed for MEDLINE]


• Sandoval R, Xue J, Tian X, Barrett K, Pilkinton M, Ucker DS, Raychaudhuri P, Kineman RD, Luque RM, Baida G, Zou X, Valli VE, Cook JL, Kiyokawa H, Colamonici OR. A mutant allele of BARA/LIN-9 rescues the cdk4-/- phenotype by releasing the repression on E2F-regulated genes. Exp Cell Res. 2006 Aug 1;312(13):2465-75. Epub 2006 Apr 25. PMID: 16730350 [PubMed - indexed for MEDLINE]

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