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癌細胞、癌症、細胞分裂周期再論
》這篇翻譯小文，有點太專業化了，不是科普，看看有多少人願意讀。作者Charles
J. Sherr研究癌症的細胞周期那年獲獎，這是獲獎發言的提要。有關內容請參考原文，Cancer
Research，60,3689-3695, July 15, 2000。本人也曾經在作者所在的研究機構St. Jude Children's Hospital，因為合作的項目，短暫的客串工作了近三個月。
J. Sherr研究癌症的細胞周期那年獲獎，這是獲獎發言的提要。有關內容請參考原文，Cancer
Research，60,3689-3695, July 15, 2000。本人也曾經在作者所在的研究機構St. Jude Children's Hospital，因為合作的項目，短暫的客串工作了近三個月。
咱也沒有什麽多的庫存，隻好把這些東西拿出來頂數量，絕不是有意賣弄。這篇文章咱讀過很多遍，曾經一度可以把這篇文章的摘要英文一字不漏的背誦下來，現在的記憶有點模糊了，已經不能保證能背誦下來了。請有心人提意見，如果有不清楚的問題，提出來看看咱能不能答複！
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癌症細胞分裂周期再論[譯文]
[哺乳類動物細胞的分裂，其DNA合成前期（G1）的準備過程極其重要]。調節這個過程的細胞因子發生遺傳變異，導致其調節功能的喪失，是絕大多數人類腫瘤產生的原因。[細胞行有絲分裂]，有絲分裂原、細胞周期因子Ｄ依賴的蛋白激酶（cdk4和cdk6）使視網膜母細胞瘤（Rb）的腫瘤抑製蛋白磷酸化，從而解除這個抑製蛋白對細胞分裂的抑製作用。使E2F等轉錄因子得以激活那些與細胞合成DNA（S期）的有關的基因，從而使細胞進入分裂周期。
對E2F有反應的下遊基因中，主要有細胞周期因子E和A。它們與cdk2結合後便使之受到激活，使細胞加速進入S期，使得細胞周期完成向前的進展。在G1期，隨著細胞周期因子D依賴性激酶的累積，它們可以將Cip/Kip等的因子，一組cdk2的抑製物俘獲。進一步協調細胞周期因子E-cdk2激活的過程，完成E2F等的轉錄程序，使得G1-S期的轉換成為可能。
“Rb通路”的對細胞分裂的抑製功能可以因Rb因子的突變而失活。另外，細胞周期蛋白依賴性激酶超水平表達，p16INK4a基因的產物表達銳減，一種細胞周期因子D依賴性激酶的抑製因子，也可以起同樣的作用。降低p27KIP1因子的表達和增加細胞周期因子E的表達，發生在許多常見的癌症的病例中，常常與不良預後相關。
ARF腫瘤抑製基因，INK4a-ARF位點的替代編碼基因產物，受有絲分裂原作用於“Rb通路”的反饋調節。超正常水平的促進生長的刺激因子，可以誘導ARF產生。通過拮抗抵消MDM2的作用，一種p53腫瘤抑製因子的負性調節因子，ARF可觸發p53依賴性的轉錄反應，從而促使初生的癌細胞生長停滯或凋亡。雖然直接損傷DNA，並不直接激活ARF，但是如果ARF的功能喪失，不僅會降低p53應對異常生長信號的抑製反應，也會增加腫瘤細胞對細胞毒性藥物和輻射治療的抵抗力。
p16因子/細胞周期因子D-cdk4/Rb因子以及ARF/Mdm2/p53因子諸環節的功能異常，如果不能說是所有的癌細胞的產生的原因，至少是絕大部分腫瘤的發病原因。這些原因在導致各個年齡段出現腫瘤和產生不同的腫瘤類型，也基本類同。
Cancer Research 60,3689-3695, July 15, 2000
Special Lecture
The Pezcoller Lecture: Cancer Cell Cycles Revisited
Charles J. Sherr
Howard Hughes Medical Institute and Department of Tumor Cell
Biology, St. Jude Children's Hospital,
Memphis, Tennessee 38105
Biology, St. Jude Children's Hospital,
Memphis, Tennessee 38105
Cell cycle and cancer
Genetic lesions that disable key regulators of G1 phase
progression in mammalian cells are present in most human cancers.
Mitogen-dependent, cyclin D-dependent kinases (cdk4 and cdk6) phosphorylate the
retinoblastoma (Rb) tumor suppressor protein, helping to cancel its
growth-inhibitory effects and enabling E2F transcription factors to activate
genes required for entry into the DNA synthetic phase (S) of the cell division
cycle.
progression in mammalian cells are present in most human cancers.
Mitogen-dependent, cyclin D-dependent kinases (cdk4 and cdk6) phosphorylate the
retinoblastoma (Rb) tumor suppressor protein, helping to cancel its
growth-inhibitory effects and enabling E2F transcription factors to activate
genes required for entry into the DNA synthetic phase (S) of the cell division
cycle.
Among the E2F-responsive genes are cyclins E and A, which
combine with and activate cdk2 to facilitate S phase entry and progression.
Accumulation of cyclin D-dependent kinases during G1 phase sequesters cdk2
inhibitors of the Cip/Kip family, complementing the effects of the E2F
transcriptional program by facilitating cyclin E-cdk2 activation at the G1-S
transition.
combine with and activate cdk2 to facilitate S phase entry and progression.
Accumulation of cyclin D-dependent kinases during G1 phase sequesters cdk2
inhibitors of the Cip/Kip family, complementing the effects of the E2F
transcriptional program by facilitating cyclin E-cdk2 activation at the G1-S
transition.
Disruption of “the Rb pathway” results from direct
mutational inactivation of Rb function, by overexpression of cyclin D dependent
kinases, or through loss of p16INK4a, an inhibitor of the cyclin D-dependent
kinases. Reduction in levels of p27Kip1 and increased expression of cyclin E
also occur and carry a poor prognostic significance in many common forms of
cancer.
mutational inactivation of Rb function, by overexpression of cyclin D dependent
kinases, or through loss of p16INK4a, an inhibitor of the cyclin D-dependent
kinases. Reduction in levels of p27Kip1 and increased expression of cyclin E
also occur and carry a poor prognostic significance in many common forms of
cancer.
The ARF tumor suppressor, encoded by an alternative reading
frame of the INK4a-ARF locus, senses “mitogenic current” flowing through the Rb
pathway and is induced by abnormal growth promoting signals. By antagonizing
Mdm2, a negative regulator of the p53 tumor suppressor, ARF triggers a
p53-dependent transcriptional response that diverts incipient cancer cells to
undergo growth arrest or apoptosis. Although ARF is not directly activated by
signals that damage DNA, its loss not only dampens the p53 response to abnormal
mitogenic signals but also renders tumor cells resistant to treatment by
cytotoxic drugs and irradiation.
frame of the INK4a-ARF locus, senses “mitogenic current” flowing through the Rb
pathway and is induced by abnormal growth promoting signals. By antagonizing
Mdm2, a negative regulator of the p53 tumor suppressor, ARF triggers a
p53-dependent transcriptional response that diverts incipient cancer cells to
undergo growth arrest or apoptosis. Although ARF is not directly activated by
signals that damage DNA, its loss not only dampens the p53 response to abnormal
mitogenic signals but also renders tumor cells resistant to treatment by
cytotoxic drugs and irradiation.
Lesions in the p16/cyclin D/cdk4 / Rb and ARF/Mdm2/p53
pathways occur so frequently in cancer, regardless of patient age or tumor
type, that they appear to be part of the life history of most, if not all,
cancer cells.
pathways occur so frequently in cancer, regardless of patient age or tumor
type, that they appear to be part of the life history of most, if not all,
cancer cells.
》謝謝來訪，評論！這個小文是咱做別的用途練手的一段翻譯。不是外行人寫的帖子，隻是增加咱的博文數量的一個帖子。沒人有多少人讀沒有關係。專業的人讀英文就夠了，不是專業的人，中文也許都不想讀，更多的情況是讀不懂。
建議換個形式，用通俗語言描述，重新起個老百姓感興趣的題目重發。