Cell cycle regulatory gene

Details Cell cycle regulatory gene Cell cycle regulatory gene

1999-06-01

2001-03-20

Fredman, Jeffrey (Department: 1655)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S024310, C536S023100, C536S023500, C435S006120, C435S091200

Reexamination Certificate

active

06204374

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to regulation of cell growth and proliferation and specifically to a novel cell cycle-related polynucleotide, 5′ALT, and novel polynucleotides encoding truncated cell cyclin inhibitors, p16
INK4A
and p15
INK4B
.
2. Description of Related Art
The growth cycle of eukaryotic cells is regulated by a family of protein kinases known as the cyclin-dependent kinases (“CDKs”). The cyclins and their associated CDKs move cells through the three phases of the growth cycle (G1, S and G2, respectively) leading to division in the mitosis phase (M). The cyclin/CDK complexes whose role in cellular proliferation has been most clearly defined to date are the cyclin D/CDK enzymes, which are believed to assist in the progression of the G1 growth cycle phase. Of these enzymes, cyclin D1 is believed to be an oncogene, whose overexpression stimulates excessive cell division through the continuous production of kinase, thus contributing to the development of cancers of, for example, the breast and esophagus. Cyclin D1 is specifically bound by CDK4 as part of a multi-protein complex that also consists of a protein known as p21 and cell nuclear antigen.
Known inhibitors of such cyclin/CDK overexpression include the tumor suppressor protein p53 and the protein product of the retinoblastoma (Rb) gene. Recently, two putative inhibitors of cell cyclins, p16
INK4A
and p15
INK4B
, were isolated (Serrano, et al.,
Nature
, 366:704, 1993; Hannon, et al,
Nature
, 371:257, 1994, respectively).
The cyclin-CDK inhibitors p16
INK4A
(CDKN2/MTS-1) and p15
INK4B
(MTS-2) are important components of cell cycle regulation. Transition through G1 is promoted by the cyclin-dependent protein kinases CDK4 and CDK6 which phosphorylate Rb resulting in release of E2F and cell cycle progression (Hunter, T. & Pines, J.,
Cell
, 79:573-582, 1994). In addition to more universal inhibitors (Morgan, D. O.,
Nature
, 374:13 1-134, 1995), these kinases are strongly inhibited by both p16
INK4A
and p15
INK4B
Isolation of the genes for these negative cell cycle regulators was quickly followed by their co-localization to chromosome 9p21, within a critical region commonly deleted in many types of human cancer (Kamb, A., et al.,
Science
, 264:436-440, 1994; Nobori, T., et al,
Nature
, 368:753-756, 1994). Familial and sporadic malignant melanomas have been consistently associated with cytogenetic abnormalities of chromosome 9p21 (Fountain, et al.,
Proc. Natl. Acad. Sci
., USA, 89:10557, 1992; Cannon-Albright, et al.,
Science
, 258:1148, 1992). Deletions of this region are also common in gliomas (Olopade, et al.,
Cancer Res
., 52:2523, 1992), lung cancers (Olopade, et al.,
Cancer Res
., 53:2410, 1993), and leukemias (Olopade, et al.,
Genomics
, 14:437, 1992). Although excellent tumor suppressor gene candidates, somatic point mutations were found to be rare in many primary human tumors with hemizygous loss of 9p21 (Cairns, et al.,
Science
245:415-416, 1994).
If the cyclins are overproduced in a cell or made at an inappropriate time, they would be expected to stimulate inappropriate cell division by keeping their partner kinases “on” when they should be turned off, a malfunction that could lead to cancer or otherwise unwanted cellular proliferation. There remains a need to identify the control signals which determine whether a cell proliferates or not.
SUMMARY OF THE INVENTION
The present invention provides novel cell cycle regulatory polynucleotides and the polypeptides they encode. The polynucleotide transcipts identified herein are a product of alternative splicing mRNA of the cyclin/CDK inhibitors, p16
INK4A
and p15
INK4B
, and a novel 5′ nucleotide sequence referred to herein as “5′ ALT”.
p16
INK4A
and p15
IN4B
colocalize to chromosome 9p21, which has been identified as a region having homozygous deletions in many tumors. 5′ ALT is shown in the present invention to also reside on chromosome 9p21, just 5′ of exon 2 of p15
IN4B
, and about 30 kb upstream from p16
INK4A
(see FIG.
2
).
In one embodiment, the present invention provides an isolated polynucleotide having the nucleotide sequence of SEQ ID NO:1, which includes the 5′ALT sequence found in the novel transcripts described herein, as well as an upstream region which is GT-rich and a downstream element which contains a highly polymorphic CA stretch.
In a second embodiment, the invention provides a polynucleotide having a 5′ALT polynucleotide operatively linked to exon 2 and exon 3 of p16
INK4A
and the polypeptide encoded by the polynucleotide. In yet another embodiments the invention provides a polynucleotide having a 5′ALT polynucleotide operatively linked to exon 2 of p15
IN4B
and the polypeptide encoded by the polynucleotide.
The identification of these novel transcripts which are associated with normal growth control and regulation of cellular proliferation provides a means for the development of more accurate diagnostic, prognostic and therapeutic regimes for disorders associated with control of cell cycle progression and cell differentiation and the loss of such control.


REFERENCES:
patent: 5739027 (1998-04-01), Kamb
Lemire et al. Journal of Biological Chemistry. vol. 264, No. 34, pp. 20206-20215, Dec. 5, 1989.*
Serrano et al., “A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4”,Nature, Dec. 16, 1993, vol. 366, pp. 704-707.

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