발암기전에 미치는 세포주기 조절 단백질들의 역할
THE ROLE OF REGULATED PROTEINS RELATED TO CELL CYCIE IN CARCINOGENESIS
배도규, 이상한, 김정희,
소속 상세정보
배도규 ( ) - 경북대학교 치과대학 구강악안면외과학교실
이상한 ( ) - 영남대학교 의과대학 생화학교실
김정희 ( ) - 영남대학교 의과대학 생화학교실
KMID : 0355619970230030374
Abstract
저자는 세포주기 조절 단백질들이 발암기전에 얼마나 중요한 역할을 하는지 밝히고자 19
례의 위선암조직을 대상으로 세포주기의 restriction checkpoint조절에 관여하는 암억제 유전
자인 CDKN2에 대한 mRNA치를 측정하여 그 발현양상을 관찰하고 세포주기 조절 단백질
인 p53, Cdk4, PCNA 및 pRb들의 단백질 발현 정도를 관찰하여 다음과 같은 결과를 얻었
다.
1. 19례의 위선암조직에서 암억제 유전자인 CDKN2의 유전자 결손 및 돌연변이는 관찰되
지 않았다. mRNA치의 발현억제는 10례로 53%에서 관찰되었다. 아울러 위선암 조직 14례
에서 western blot으로 restriction checkpoint 단백질을 분석하였으며 p53은 38%에서 과발
현이 관찰되었고 Cdk4는 모든 위암조직에서 고르게 발현되었으며 PCNA는 대조군에 비해
모두 발현이 억제되었다.
2. 상기 단백질들의 발현을 면역 조직화학분석 법으로 파라핀 고정된 14례의 위선암 조직
을 대상으로 관찰하였으며 p53은 세포핵에 강한 면역반응을 보였고 Cdk4는 핵과 cytoplasm
에 모두 발현되었고 핵내가 더 강하게 나타났으며 PCNA는 정상세포 보다는 암세포에서 다
소 강하게 관찰되었다. pRb는 Cdk4나 PCNA 보다는 약한 반응을 보였으나 정상세포 보다
는 강하게 발현되었다. 14 례의 위선암환자 고정시료로 부터 과발현 결과는 p53은 8례로
57.1%, Cdk4는 2례로 14.3%, PCNA는 1례로 7.1% pRb는 10례로 71.4%로 관찰되었다. 이상
의 결과 위암에서의 CDKN2 유전자 결손은 관찰되지 않았으나 단백질 발현 감소로 인하여
발현이상이 초래되고 세포주기의 G1기 부위인 restriction checkpoint의 이상으로 암발생이
유도되었다고 할 수 있다.
#초록#
The cell cycle is composed of G1, S, G2 and M phase. The transitions between
different phases are regulated at checkpoint such as Start(restriction), S phase and
mitotic checkpoint. These checkpoints are regulated by specific cyclins and
Cdks(cyclin-dependent kinases). Especially, Start checkpoint in late G1 is though to be
very important in control of cell cycle.
In this study, it was shown various CDKN2(p16ink4A) alteration,
including deletions, mutations, down regulations, and performed differential expression of
p53, Cdk4, PCNA and pRb in stomach cancer tissues.
1. The frequency of CDKN2 mutations was not observed in the 19 primary stomach
cancer tissues. In contrast to the mutations of CDKN2, mRNA levels was showed by
Northern blot analysis that expression of CDKN2 was absent or decreased in 10 of the
19(53%) primary stomach adenocarcinoma. Western blot analysis was performed to
determine the differential expression of p53, Cdk4, PCNA related to Start checkpoint.
Overexpression of p53 was shown 38%, Cdk4 was expressed in all each specimens, and
expression of PCNA was not shown.
2. As the other method to determine the differential expression of p53, Cdk4, PCNA
and pRb, immunohistochemical analyses were performed on each 14 formalin-fixed and
paraffin embedded tumor tissues of stomach adenocarcinoma. p53 overexpression was
showed to clear nuclear staining only in tumor cells not in nonneoplastic cells. In
staining for cdk4, the tumor was considered to be cdk4 positive if there was nuclear
staining in tumor cells, regardless of cytoplasmic staining. PCNA staining for carcinoma
tissues showed more intense nuclear staining in tumor cells than in nonneoplastic cells.
pRb overexpression was show in tumor cells. Significant differences were observed in
the expression of the proteins among the cancers from different anatomic site.
Overexpression of adenocarcinomas had high rate of p53(57.1%) and pRb(71.4% ), and
low late of cdk4(7.1% ) and PCNA(14.3% ), As these results, deletion of CDKN2 gene
in human stomach cancer was not observed but mRNA expression was down regulated
in restriction checkpoint, G1 phase. Inactivation of the CDKN2 gene due to
hypermethylation may play an important role in development of cancer. And one of the
abnormalities in p53, Cdk4, PCNA or pRb function occurs very common in various
cancers, especially oral adenocarcinoma, osteosarcoma and squemous cell carcinoma,
suggest that components in restriction checkpoint also play an critical role in the
carcinogenesis and progression of cancers.
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