Kenneth B. Marcu
Ph.D., University at Stony Brook, 1975
Professor, Departments of Biochemistry and Cell Biology, Microbiology and
Pathology
Research Interests: Mammalian gene regulation and function
The c-Myc polypeptide product encodes a basic-helix-loop-helix class transcription
factor which regulates genes effecting cellular growth and differentiation;
and its deregulated expression potentially contributes to either neoplasia
or apoptosis. We have cloned and characterized a zinc finger type transcription
factor, MAZ (MYC Associated Zinc Finger) which binds with high specificity
to an essential control element (ME1a1) within the MYC gene's major P2 promoter.
The ME1a1 site is necessary for efficient initiation and transcriptional
elongation of MYC P2 transcripts. MAZ/ME1a1-like binding sites are also
involved in the transcriptional pausing/termination of human complement
gene transcripts and may also constitute part of the murine CD4 gene's promoter
as well. The MAZ polypeptide contains multiple functional domains and appears
to be expressed in alternative forms in vivo. We are elucidating the role
of MAZ in MYC transcriptional control in growing and differentiating cells
and the contributions of the ME1a1 element for regulated c-MYC expression
in normal tissues and in murine development.
In a second project, we are studying the regulated recombination of immunoglobulin
heavy chain constant region (CH) genes during the maturation of B lymphocytes.
CH gene switches are manifested by DNA deletions facilitated by stretches
of tandemly repetitive sequences of limited homology (switch or S regions)
which are positioned about 2 kb 5' of each CH gene. We are defining the
molecular requirements for CH gene switching by introducing switch-recombinase
substrates into B lymphoid cell lines via retroviral vectors and employing
positive and negative selection strategies to clone genes encoding components
of the switch-recombinase complex.
In a third project, we are defining the in vivo properties of PANG (plasmacytoma-associated-neuronal-glycoprotein),
a new member of the neuronal adhesion molecule family. Ectopic PANG expression
by endogenous murine retroviruses may contribute to malignant progression
of plasma cell tumors; but it normally likely functions to establish unique
axonal migratory patterns in brain development.
In a fourth project, we are defining the in vivo properties of CHUK, a novel
serine threonine type protein kinase. In addition to an amino terminal kinase
catalytic domain, CHUK also contains multiple amphipathic, alpha helical
domains that likely function as interfaces for protein-protein interactions
with specific transcription factors of the helix-loop-helix and leucine
zipper families. We are investigating the provocative hypothesis that CHUK
may function in a number of diverse cell types by transducing signals from
the cytoplasm to the nucleus and thereby modulate gene expression in response
to external stimuli.
Bossone, S.A., Asselin, C., Patel, A.J. and Marcu, K.B. (1992) MAZ, a novel
zinc finger protein binds to C-MYC and C2 gene sequences regulating transcriptional
initiation and termination. Proc. Natl. Acad. Sci. USA 89: 7452-7456.
Connelly, M.A., Grady, R.C., Mushinski, J.F. and Marcu, K.B. (1994) PANG,
a gene encoding a neuronal glycoprotein, is ectopically activated by intracisternal
A-type particle long terminal repeats in murine plasmacytomas. Proc. Natl.
Acad. Sci. USA 91: 1337-1341.
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