1: Leuk Lymphoma. 2001 Jan;40(3-4):267-78. 

HTLV-I Tax related dysfunction of cell cycle regulators and oncogenesis of adult
T cell leukemia.

Arima N, Tei C.

First Department Internal Medicine, Faculty of Medicine, Kagoshima University,
Japan. nao@med6.kufm.kagoshima-u.ac.jp

HTLV-I is causually related to the oncogenesis of adult T cell leukemia (ATL).
However, the precise mechanism of HTLV-I oncogenesis is unclear. HTLV-I Tax
protein functions as an activator of various cellular genes, including IL-2,
IL-2 receptor-alpha, and c-fos through the activation of nuclear transfer
factors such as NF-kappaB and SRF, and also potently activates trascription of
viral genes through CREB/ATF sites in the viral LTR. However, Tax activation of
HTLV-I infected T cells through the above pathways induces polyclonal
proliferation of the cells in vitro; Tax however may function only transiently
in the immediate post-infection period following infection in vivo. The long
latent period of 60 years from infection to onset of disease suggests other
mechanisms for ATL oncogenesis. Recent studies suggest that the malignant
transformation of ATL is a multi-hit phenomena, suggesting that discrete genetic
events are responsible for ATL oncogenesis. These genetic events could be
responsible for the different stages of ATL: smoldering, chronic, lymphoma, and
acute type, p16 and p53 genes are important negative regulators of the cell
cycle and are often found to be mutated in neoplasms. Recent studies including
ours demonstrated a high frequency of alteration of these two genes in primary
ATL cells. Furthermore, alteration of the two genes is associated with acute but
not chronic type ATL. In addition, p16 gene alteration is linked to the growth
rate of ATL cells, suggesting that the alteration of these cell cycle regulatory
genes may be related to progression from smoldering or chronic to acute or
lymphoma type ATL. Tax may be involved in mutagenesis of these genes through
suppression of DNA-beta polymerase gene expression during the process from
latent period to acute/lymphoma type. Once transformation occurs, activation of
the pathway between Tax and the three nuclear transfer factors, NF-kappaB, SRF,
and CREB/ATF, contributes to establish the aggressive manifestations of
acute/lymphoma type ATL cells.

Publication Types:
    Review
    Review, Tutorial

PMID: 11426548 [PubMed - indexed for MEDLINE]


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2: Biochem Cell Biol. 1996;74(4):523-34. 

Regulation of transcription factor activity during cellular aging.

Wheaton K, Atadja P, Riabowol K.

Department of Medical Biochemistry, University of Calgary Health Sciences
Centre, AB, Canada.

Several lines of evidence suggest that the limited replication potential of
normal human cells is due to the presence of an intrinsic genetic programme.
This "senescence programme" is believed to reduce the incidence of cancer by
limiting the growth of most of the transformed cells arising in vivo, although
some cells do escape senescence becoming both immortalized and transformed. Here
we review the literature that describes the senescence process in terms of gene
expression and the regulation of gene expression by a variety of mechanisms
affecting transcription factor activity. We focus on regulation of the c-fos
gene through posttranslational modification of the serum response factor (SRF)
as an example of altered gene expression during cellular aging.

Publication Types:
    Review
    Review, Tutorial

PMID: 8960358 [PubMed - indexed for MEDLINE]


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