Raudel Sandoval, PhD
Research Assistant Professor
Furthering our present understanding of cell cycle
by elucidating new regulatory mechanisms is critical for the subsequent
development of novel therapeutic agents against cancer. The G1 phase
of the cell cycle is an important intersection where positive and
negative regulatory signals converge to control cell cycle progression.
The negative regulation of the cell cycle is coordinated by the
cyclin-dependent kinase (CDK) inhibitors and the family of pocket proteins.
These proteins play a critical role during the G0/G1 phase of the cell
cycle by negatively regulating the expression of E2F-responsive genes
that are required for the G1/S transition. Presently, my work focuses
on the negative regulation of the cell cycle by a mammalian form of C.
elegans lin-9 and Drosophila
mip130. In C. elegans, LIN-9 functions downstream of the
mammalian equivalent of CDK4 in a pathway that regulates cell proliferation. Drosophila Mip130,
along with Mip120 and Mip40, interacts with Drosophila Myb in
a stable complex to regulate gene replication and transcription.
The mammalian lin-9 homologue
also appears to act downstream of cyclin D/CDK4 in mammalian cells.
This is supported by the fact that over-expression of LIN-9 has
an inhibitory effect on cell proliferation which is partially blocked
by co-expression of cyclin D1 and by the partial rescue of phenotypic
alterations in CDK-null mice by expression of a mutant form of LIN-9
lacking amino acids 1-84 (Æ84LIN-9). Moreover, we have determined
that LIN-9 interacts with p107/p130, members of the pocket protein
family and targets for CDK4 phosphorylation, and E2F4. Additionally, we
have recently identified the stable interaction between LIN-9 and mammalian
homologues of Drosophila Mip120
and Mip40. This complex of Drosophila mip homologues potentially
acting in concert with p107/p130 and E2F4 to regulate mammalian
gene transcription is unique and can further develop our present
understanding of mammalian cell cycle regulation.
1856 W. Polk St.
Sandoval, R., J. Xue, M.
Pilkinton, D. Salvi, H, Kiyokawa, and O. R. Colamonici.Ê Different
requirements for the cytostatic and apoptotic effects of type
I IFNs: Induction of apoptosis requires ARF, but not p53 in osteosarcoma
cell lines. J.
Biol. Chem.Ê 279:32275-32280, 2004.
Sandoval, R., J. Xue, K.
Barrett, M. Pilkinton, D. S. Ucker, P. Raychaudhuri, R. D. Kineman,
R. M. Luque, G. Baida, X. Zou, V.E. Valli, J. L.Cook, H. Kiyokawa,
and O. R. Colamonici. A mutant allele of BARA/LIN-9 rescues
the CDK4Ð/Ð phenotype
by releasing the repression on E2F-regulated genes. Exp. Cell
Pilkinton, M., R. Sandoval,
J. Song, S. A. Ness, and O. R. Colamonici.Ê Mip/LIN-9 regulates the expression
of B-MYB, and the inductionÊof cyclin A, cyclin B and CDK1.Ê J.
Biol. Chem.Ê 282:168-175, 2007.